7-ethynylisoindolin-1-ones and its derivatives as inhibitors of STAT6 and therapeutic methods using the same

Abstract

The disclosure relates to inhibitors of signal transducer and activator of transcription (STAT) proteins and use thereof for the treatment of disease.

Description

7-ETHYNYLISOINDOLIN-1-ONES AND ITS DERIVATIVES AS INHIBITORS OF STAT6 AND THERAPEUTIC METHODS USING THE SAMECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit of priority to U.S. Provisional Patent Application Nos.63 / 752,530, filed January 31, 2025 and 63 / 852,567, filed July 28, 2025, all of which are hereby incorporated herein by reference in their entireties for all purposes.FIELD

[0002] The disclosure relates generally to compounds that inhibit the activity of signal transducer and activator of transcription (STAT) proteins, and methods of using such compounds as treatments for disease.BACKGROUND

[0003] The signal transducer and activator of transcription (STAT) proteins play important roles in biological processes. STAT proteins promote fundamental cellular processes, including cell growth and differentiation, development, apoptosis, immune responses, and inflammation.

[0004] The STAT protein family includes the following members: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6. Structurally, STAT proteins share five domains: an amino-terminal domain, a coiled-coil domain, a DNA-binding domain, an SH2 domain, and a carboxy -terminal transactivation domain. The transactivation domain contains one or two amino acid residues that are crucial for the activity of the STAT protein; phosphorylation of a particular tyrosine residue promotes dimerization, whereas phosphorylation of a particular serine residue enhances transcriptional activation. Activation of STAT6, like other STAT proteins, is triggered upon binding of hormones, immunomodulatory cytokines or growth factors to specific receptors on the cell surface. Once activated, the phosphorylation of a C-terminal tyrosine residue occurs, leading to translocation and transmission of signals from the cytosol to the nucleus, resulting in activation of gene expression.

[0005] STAT6 is known as an important transcriptional factor transmitting signals of interleukin-4 (IL-4) and interleukin- 13 (IL-13), and plays a vital role in the differentiation of T- helper type 2 (Th2) cells. STAT6 is primarily activated in the Janus Kinase (JAK) pathway byDB1 / 166057797.1 1Docket No. 133447-5010-WOinflammatory cytokines, interleukin-4 (IL4) and interleukin-13 (IL13), and their cognate receptors, which are produced by Th2 cells, mast cells and basophils. Thus, STAT6 is implicated in driving type 2 immune responses and is involved in the development of allergic and inflammatory diseases.

[0006] The need for STAT inhibitors and STAT6-selective inhibitors that can be used for therapeutic purposes in the treatment of allergies / allergic diseases, inflammation / inflammatory diseases, and / or autoimmune diseases remains unmet in the art.SUMMARY

[0007] In aspects, the disclosure provides a compound of formula (IA), or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof:wherein in formula (IA): Ai is N or CR1; A2 is N or CR2; A3 is N or CR3; R1, R2, and R3are each independently selected from H, deuterium, halide, -CN, -ORa, -N(Ra)2, -NO2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 6-membered heterocycloalkyl; ring A is aryl or heteroaryl; ring B is selected from aryl, cycloalkyl, heteroaryl, and heterocycloalkyl; R4and R5are independently at each occurrence selected from deuterium, halide, -CN, trimethylsilanyl, oxo, -ORa, -SRa, -S(O)tRa, -OC(O)Ra, -N(Ra)2, -C(O)Ra, - C(O)ORa, -C(O)N(Ra)2, -NO2, -OC(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, - N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -C(O)N(Ra)S(O)tRa, -S(O)tORa, - S(O)tN(Ra)2, -S(O)tN(Ra)C(O)Ra, -P(O)(ORa)2, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C8 cycloalkyl, optionally DB1 / 166057797.1Docket No. 133447-5010-WOsubstituted 3- to 8-membered heteroalkyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocycloalkyl; m and n are each independently selected from 0, 1, 2, 3, and 4; t is 1 or 2; R6and R6are each independently selected from H, deuterium, halide, -CN, -ORa, -N(Ra)2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-C6haloalkyl, optionally substituted C₆-C₁₂ aryl, optionally substituted C₃-C₈ cycloalkyl, optionally substituted 3- to 8-membered heteroalkyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocycloalkyl; or R6and R6are taken together to form =C(Rb)2; Rais independently at each occurrence selected from H, deuterium, -OH, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted3- to 6-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl; or two Ragroups are taken together with the atom to which they are attached to form optionally substituted 5- to 6-membered heteroaryl or optionally substituted 3- to 6-membered heterocycloalkyl; and Rbis independently at each occurrence selected from H, deuterium, halide, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heteroalkyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocycloalkyl.

[0008] In embodiments, the compound of formula (IA), or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, is a compound having a structure according to formula (IIA):wherein in formula (IIA): Ai is N or CR1; A2 is N or CR2; A3 is N or CR3; R1, R2, and R3are each independently selected from H, halide, -ORa, -N(Ra)2, optionally substituted C1-C3 alkyl, DB1 / 166057797.1Docket No. 133447-5010-WOoptionally substituted C1-C3 haloalkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 5-membered heterocycloalkyl; A4 is N or CR41; A? is N or CR51; Yi and Y2 are each independently selected from N and CR'; or Yi is absent, and Y2 is selected from NRb, O, and S; R41, R51, and R' are each independently selected from H, halide, -CN, -ORa, -S(O)tRb, -OC(O)Rb, -N(Rb)2, -C(O)Rb, -C(O)N(Rb)2, -N(Ra)C(O)Rb, -S(O)tN(Rb)2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 haloalkyl, optionally substituted C3-C4 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, and optionally substituted 3- to 4-membered heterocycloalkyl; ring B is selected from phenyl, 5- to 6-membered heteroaryl, and 3- to 10-membered heterocycloalkyl; R4is selected from -S(O)tRa, -OC(O)Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa, -C(O)N(Ra)S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, -S(O)tN(Ra)C(O)Ra, substituted C1-C4 alkyl, substituted C6-C10aryl, substituted C3-C8 cycloalkyl, substituted 5- to 10-membered heteroaryl, and substituted 3- to 10-membered heterocycloalkyl; R5is independently at each occurrence selected from halide, -CN, oxo, -ORa, - SRa, -S(O)tRa, -OC(O)Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -NO2, -OC(O)N(Ra)2, - N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, - C(O)N(Ra)S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, -S(O)tN(Ra)C(O)Ra, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl; n is 1, 2, or 3; t is 1 or 2; R6and R6are each independently selected from H, deuterium, halide, -CN, -ORa, -N(Ra)2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 haloalkyl, optionally substituted phenyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 8-membered heterocycloalkyl; or R6and R6' are taken together to form =C(Rb)2; Rais independently at each occurrence selected from H, -OH, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 haloalkyl, optionally substituted phenyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 6-membered heterocycloalkyl; or two Ragroups are taken together with the atom to which they are attached to form optionally substituted5- to 6-membered heteroaryl or optionally substituted 3- to 6-membered heterocycloalkyl; and RbDB1 / 166057797.1Docket No. 133447-5010-WOis independently at each occurrence selected from H, deuterium, halide, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 haloalkyl, optionally substituted phenyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 6-membered heterocycloalkyl.

[0009] In embodiments, R4is a moiety of formula (IIIA):OM 1Z\IZ2HZ3)\Z / P v 'Vq (IIIA),wherein in formula (IIIA): = is a single bond or a double bond; A₆ is selected from N, C, and CH; X is selected from NRdor N; C(Rd)2 or CRd; O; and S; Zi, Z2, and Z3 are each independently selected from NRd, N, C(Rd)2, CRd, C(O), O, and S; p and q are each independently selected from 0 and 1; and Rdis independently at each occurrence selected from H, halide, -CN, -ORa, -N(Ra)2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 haloalkyl, optionally substituted phenyl, optionally substituted C3-C6 cycloalkyl, optionally substituted3- to 6-membered heteroalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 6-membered heterocycloalkyl.

[0010] In embodiments, the compound of formula (IA) and / or formula (IIA), or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, is a compound having a structure according to formula (IVA):(IVA),DB1 / 166057797.1Docket No. 133447-5010-WOwherein in formula (IVA): ring B is selected from phenyl, pyridine, pyrazine, pyrimidine, pyridazine, triazine, tetrazine.

[0011] In embodiments, R4is a moiety of formula (VA):(VA),wherein in formula (VA): Rdis independently at each occurrence selected from H, halide, -ORd, optionally substituted C1-C3 alkyl, -CD3, C1-C2 haloalkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 5-membered heterocycloalkyl; and Rdis independently at each occurrence selected from H, optionally substituted C1-C3 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl.

[0012] In embodiments, the compound of formula (IA), formula (IIA), and / or formula (IVA), or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, is a compound having a structure according to formula (VIA):R51R41R2N \I N RN^ / (R5)n (VIA), wherein in formula (VIA): R1is selected from H, halide, and optionally substituted C1-C3 alkyl; R2is selected from H, halide, -CN, -OH, -OCH3, -NHz, -N(CH3)z, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 haloalkyl, optionally substituted C3-C4 cycloalkyl, and optionally substituted 3- to 4-membered heterocycloalkyl; R3is selected from H, halide, and optionally substituted C1-C3 alkyl; R41is selected from H, F, Cl, Br, -CN, -OCH3, -S(O)zCH3, -DB1 / 166057797.1Docket No. 133447-5010-WOC(O)CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH(CH3)2, and -CH2N(CH3)2; R51is selected from H, F, Cl, Br, -CN, -OCH3, -S(O)2CH3, -C(O)CH3, -CH3, -CH2CH3, -CH2CH2CH3, - CH2CH(CH3)2, and -CH2N(CH3)2; RYare each independently selected from H, F, Cl, Br, -CN, - OCH3, -S(O)2CH3, -C(O)CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH(CH3)2, and - CH2N(CH3)2; Rdis independently at each occurrence selected from H, halide, -ORd, optionally substituted Ci-C3alkyl, -CD3, Ci-C2haloalkyl, optionally substituted C3-Cs cycloalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 5-membered heterocycloalkyl; Rdis independently at each occurrence selected from H, optionally substituted Ci-C3alkyl, optionally substituted C₃-C₈ cycloalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl; R5is independently at each occurrence selected from halide, -CN, oxo, -ORa, -SRa, -S(O)tRa, -OC(O)Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -NO2, -OC(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, - N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -C(O)N(Ra)S(O)tRa, -S(O)tORa, - S(O)tN(Ra)2, -S(O)tN(Ra)C(O)Ra, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-Cs cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl; n is 1, 2, or 3; t is 1 or 2; R6and R6are each independently selected from H, deuterium, halide, -CN, -ORa, -N(Ra)2, optionally substituted Ci-C3alkyl, optionally substituted Ci-C3haloalkyl, optionally substituted phenyl, optionally substituted C₃-C₆ cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 8-membered heterocycloalkyl; or R6and R6' are taken together to form =C(Rb)2; and Rais independently at each occurrence selected from H, -OH, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 haloalkyl, optionally substituted phenyl, optionally substituted C3-C6cycloalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 6-membered heterocycloalkyl; or two Ragroups are taken together with the atom to which they are attached to form optionally substituted 5- to 6-membered heteroaryl or optionally substituted3- to 6-membered heterocycloalkyl.DB1 / 166057797.1Docket No. 133447-5010-WO

[0013] In embodiments, R4is a moiety of formula (VIIA):O°^Rd’ (VIIA),wherein in formula (VIIA): Rdis selected from H, optionally substituted C1-C3 alkyl, -CD3, optionally substituted C3-C4 cycloalkyl, and optionally substituted 3- to 4-membered heterocycloalkyl; and Rd' is selected from H, optionally substituted C1-C3 alkyl, optionally substituted C3-C8 cycloalkyl, and optionally substituted 3- to 10-membered heterocycloalkyl.

[0014] In embodiments, the compound of formula (IA), formula (IIA), formula (IVA), and / or formula (VIA), or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocry stal, or prodrug thereof, is a compound having a structure according to formula (VIIIA):p R2°^Rd' TV° R6'(R5)n (VIIIA),wherein in formula (VIIIA): R2is selected from H, Cl, Br, F, -CN, -OCH3, -N(CH3)2, -CH3, - CF3, cyclopropyl, and oxetanyl; Rdis selected from H, optionally substituted C1-C3 alkyl, -CD3, optionally substituted C3-C4 cycloalkyl, and optionally substituted 3- to 4-membered heterocycloalkyl; Rdis selected from H, optionally substituted C1-C3 alkyl, optionally substituted C3-C8 cycloalkyl, and optionally substituted 3- to 10-membered heterocycloalkyl; R5is independently at each occurrence selected from F, -CN, -CH3, -C(O)N(R5a)2, optionally substituted C3-C8 cycloalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 8-membered heterocycloalkyl; R5ais independently at each occurrence selected from H, optionally substituted C1-C3 alkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 6-membered heterocycloalkyl; n is 1, 2, or 3; R6and R6are each DB1 / 166057797.1Docket No. 133447-5010-WOindependently selected from H, deuterium, halide, -CN, -OR6a, -NHR6a, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 haloalkyl, optionally substituted phenyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 8-membered heterocycloalkyl; or R6and R6are taken together to form=C(R6b)2; R6ais independently at each occurrence selected from H, optionally substituted C1-C3 alkyl, optionally substituted C1-C4 haloalkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocycloalkyl; and R6bis independently at each occurrence selected from H, deuterium, halide, C1-C3 alkyl, and C1-C3 haloalkyl.

[0015] In one aspect, the disclosure provides a pharmaceutical composition comprising a compound described herein (e.g., a compound of formula (IA), formula (IIA), formula (IVA), formula (VIA), formula (VIIIA), or formula 1001-1351), or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, and a physiologically compatible carrier medium.

[0016] In aspects, the disclosure provides a method of treating a disease or disorder in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound described herein e.g., a compound of formula (IA), formula (IIA), formula (IVA), formula (VIA), formula (VIIIA), or formula 1001-1351), or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. In aspects, the disclosure provides a method of treating a disease or disorder in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a composition described herein. In some embodiments, the disease or disorder is selected from an allergic disease, an inflammatory disease, and an autoimmune disease. In some embodiments, the disease or disorder is alleviated by inhibiting signal transducer and activator of transcription (STAT) protein activity in the patient. In some embodiments, the disease or disorder is alleviated by inhibiting STAT6 protein activity in the patient.

[0017] In some embodiments, the compound (e.g., a compound according to formula (IA), formula (IIA), formula (IVA), and formula 1001-1351), or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, has a cellular activity of at least about 10 μM as measured by an in vitro cellular assay. In some embodiments, the compound (e.g., a compound according to formula (IA), formula (IIA), formula (IVA), and formula 1001-DB1 / 166057797.1Docket No. 133447-5010-WO1351), or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, has a Kd of about 1 pM or less.DETAILED DESCRIPTION

[0018] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs. All patents and publications referred to herein are incorporated by reference in their entireties.Definitions

[0019] Unless defined otherwise, all technical and scientific terms used in the description of the present disclosure have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs. All patents and publications referred to herein are incorporated by reference in their entireties.

[0020] “Alkyl” refers to a straight or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, containing no unsaturation, and having from 1 to 20, or more, carbon atoms (e.g., C1-20 alkyl). A numerical range may be given, e.g., C1-20, Ci-is, C1-16, C1-14, C1-12, Ci-10, C1-8, C1-6, C1-4, or C1-3 alkyl, which refers to the total number of carbon atoms in the in the alkyl chain. Whenever it appears herein, a numerical range such as “1 to 10” refers to each integer in the given range, e.g., “1 to 10 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the definition is also intended to cover the occurrence of the term “alkyl” where no numerical range is specifically designated. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, / / -butyl, isobutyl, sec-butyl isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl and decyl. The alkyl moiety may be attached to the rest of the molecule by a single bond, such as for example, methyl (Me), ethyl (Et), / / -propyl (nPr), 1 -methylethyl (isopropyl), / / -butyl, / / -pentyl, 1,1 -dimethyl ethyl ( / -butyl) and 3 -methylhexyl. “Alkylene” by itself or as part of another term, as used herein, refers to an alkyl group, as defined above, linking at least two other groups (i.e., a divalent alkyl radical). The two moieties linked to the alkylene group can be attached to the same carbon atom or different carbon atoms of the alkylene group. Unless stated otherwise specifically in the specification, an alkyl group (or alkylene group) is optionally substituted by one or more substituents whichDB1 / 166057797.1Docket No. 133447-5010-WOindependently are: deuterium, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trifluoromethyl, trifluoromethoxy, trimethylsilanyl, pentafluorosulfanyl, -OR', -SR', -OC(O)R', -N(R')2, -C(O)R', -C(O)OR', -OC(O)N(R')2, -C(O)N(R')2, -N(R')C(O)OR', -N(R')C(O)R', -N(R')S(O)tR' (where t is 1 or 2), -N(R')C(O)N(R')2, -N(R')C(NR')N(R')2, -S(O)tR' (where t is 1 or 2), -S(O)tOR' (where t is 1 or 2), -S(O)tN(R')2 (where t is 1 or 2), or -PO(OR')2, where each R' is independently hydrogen, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0021] “Alkylaryl” refers to an -(alkyl)aryl radical where aryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl respectively. “Benzyl” is a non-limiting example of an alkylaryl group.

[0022] “Alkylcycloalkyl” refers to an -(alkyl)cycloalkyl radical where cycloalkyl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and alkyl respectively.

[0023] “Alkylheteroaryl” refers to an -(alkyl)heteroaryl radical where heteroaryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroaryl and alkyl respectively.

[0024] “Alkylheterocycloalkyl” refers to an -(alkyl)heterocycloalkyl radical where alkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heterocycloalkyl and alkyl respectively.

[0025] “Alkenyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from 2 to 20, or more, carbon atoms (z.e., (C2-2o)alkenyl or C2-20 alkenyl). A numerical range may be given, e.g., C2-20, C2-18, C2-16, C2-14, C2-12, C2-10, C2-8, C2-6, or C2-4 alkenyl, which refers to the total number of carbon atoms in the in the alkenyl chain. Whenever it appears herein, a numerical range such as “2 to 10” refers to each integer in the given range - e.g., “2 to 10 carbonDB1 / 166057797.1Docket No. 133447-5010-WOatoms” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. The alkenyl moiety may be attached to the rest of the molecule by a single bond, such as for example, ethenyl (i.e., vinyl), prop-l-enyl (z.e., allyl), but-l-enyl, pent-l-enyl and penta- 1,4-dienyl. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more substituents which independently are: deuterium, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, heteroalkyl, acylsulfonamido, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trifluoromethyl, trifluoromethoxy, trimethylsilanyl, pentafluorosulfanyl, -OR', -C(O)R', - OC(O)R', -C(O)OR',-OC(O)N(R')2, -C(O)N(R')2, -N(R')2, -N(R')C(O)R', -N(R')C(O)OR', -N(R')S(O)tR' (where t is 1 or 2), -N(R')C(O)N(R')2, -N(R')C(NR')N(R')2, -SR', -S(O)tR' (where t is 1 or 2), -S(O)tOR' (where t is 1 or 2), -S(O)tN(R')2 (where t is 1 or 2), or -PO(OR')2, where each R' is independently hydrogen, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0026] “Alkynyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from 2 to 20, or more, carbon atoms (i.e., (C2-20)alkynyl or C2-20alkynyl). A numerical range may be given, e.g., C2-20, C2-18, C2-16, C2-14, C2-12, C2-10, C2-8, C2-6, or C2-4alkynyl, which refers to the total number of carbon atoms in the in the alkynyl chain. Whenever it appears herein, a numerical range such as “2 to 10” refers to each integer in the given range - e.g., “2 to 10 carbon atoms” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. The alkynyl may be attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl and hexynyl. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more substituents which independently are: deuterium, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, heteroalkyl, acylsulfonamido, alkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trifluoromethyl, trifluoromethoxy, trimethylsilanyl, pentafluorosulfanyl, -OR', -SR', -OC(O)R', -N(R')2, -C(O)R', -C(O)OR', - DB1 / 166057797.1Docket No. 133447-5010-WOOC(O)N(R')2, -C(O)N(R')2, -N(R')C(O)OR', -N(R')C(O)R', -N(R')S(O)tR' (where t is 1 or 2), - N(R')C(O)N(R')2, -N(R')C(NR')N(R')2, -S(O)tR' (where t is 1 or 2), -S(O)tOR' (where t is 1 or 2), -S(O)tN(R')2(where t is 1 or 2), or -PO(OR')2, where each R' is independently hydrogen, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0027] “Acyl” refers to a -(C=O)R radical group, wherein the group is attached to the parent structure through the carbonyl functionality, and R is selected from alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl. If the R radical is heteroaryl, heteroalkyl, or heterocycloalkyl, the hetero ring or chain atoms contribute to the total number of chain or ring atoms. Unless stated otherwise specifically in the specification, the R of an acyl group (i.e., -(C=O)R) is optionally substituted by one or more substituents which independently are: deuterium, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trifluoromethyl, trifluoromethoxy, trimethylsilanyl, pentafluorosulfanyl, -OR', -SR', -OC(O)R', -N(R')2, -C(O)R', -C(O)OR', -OC(O)N(R')2, -C(O)N(R')2, -N(R')C(O)OR', -N(R')C(O)R', -N(R')S(O)tR' (where t is 1 or 2), -N(R')C(O)N(R')2, -N(R')C(NR')N(R')2, -S(O)tR' (where t is 1 or 2), -S(O)tOR' (where t is 1 or 2), -S(O)tN(R')2 (where t is 1 or 2), or -PO(OR’)2, where each R' is independently hydrogen, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0028] “Acyloxy” refers to a -O(C=O)R radical group, wherein R is alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl. If the R radical is heteroaryl, heteroalkyl, or heterocycloalkyl, the hetero ring or chain atoms contribute to the total number of chain or ring atoms. Unless stated otherwise specifically in the specification, the R of an acyloxy group i.e., -O(C=O)R) is optionally substituted by one or more substituents which independently are: deuterium, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, heteroalkyl, acylsulfonamido, alkenyl,DB1 / 166057797.1Docket No. 133447-5010-WOalkynyl, cycloalkyl, cycloalkyl alkyl, heterocycloalkyl, heterocycloalkylalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trifluoromethyl, trifluoromethoxy, trimethylsilanyl, pentafluorosulfanyl, -OR', -SR', -OC(O)R', -N(R')2, -C(O)R', -C(O)OR', -OC(O)N(R')2, -C(O)N(R')2, -N(R')C(O)OR', -N(R')C(O)R', -N(R')S(O)tR' (where t is 1 or 2), -N(R')C(O)N(R')2, -N(R')C(NR')N(R')2, -S(O)tR' (where t is 1 or 2), -S(O)tOR' (where t is 1 or 2), -S(O)tN(R')2(where t is 1 or 2), or -PO(OR’)2, where each R' is independently hydrogen, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroaryl alkyl.

[0029] “Acylsulfonamide” refers to the group -C(=O)NR'-S(=O)2R', where each R' is independently hydrogen, deuterium, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0030] “Carboxaldehyde” refers to a -(C=O)H radical group.

[0031] “Carbonyl” refers to a -C(=O)- functional group.

[0032] “Carboxyl” refers to a -(C=O)OH radical.

[0033] “Cyano” refers to a -CN radical.

[0034] “Cycloalkyl” refers to a cyclic hydrocarbon radical consisting of only carbon and hydrogen atoms, which may be completely saturated or partially unsaturated, and having from 3 to 12 ring atoms (i.e., (C3-12)cycloalkyl or C3-12cycloalkyl). Whenever it appears herein, a numerical range such as “3 to 12” refers to each integer in the given range - e.g., “3 to 12 carbon atoms” means that the cycloalkyl group may consist of 3 carbon atoms, etc., up to and including 12 carbon atoms. A cycloalkyl group can be a single ring (e.g., monocyclic) or multiple rings (e.g., polycyclic). Illustrative examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, and the like. Polycyclic cycloalkyl groups are composed of 2 or more rings (e.g., bicyclic, tricyclic or tetracyclic ring system) and include fused cycloalkyl, bridged cycloalkyl, and spiro cycloalkyl ring systems. A fused cycloalkyl group refers to a polycyclic cycloalkyl ring system in which 2 or more rings share adjacent pairs of ring atoms. Illustrative examples of fused cycloalkyl groups include, but are not limited to,DB1 / 166057797.1Docket No. 133447-5010-WObicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[3.1,0]hexyl, bicyclo[3.2.0]heptyl, octahydropentalenyl, bicyclo[4.2.0]octyl, octahydro-lH-indenyl, decahydronaphthalenyl, decahy droazul eny 1, decahydro- 1 H-b enzo

[0007] annul eny 1, dodecahydro- 1 H-phenal eny 1, tetradecahydroanthracenyl, and the like. A bridged cycloalkyl group refers to a polycyclic cycloalkyl ring system in which a cycloalkyl ring contains at least one linkage of one or more atoms connecting non-adjacent ring atoms of the cycloalkyl. Illustrative examples of bridged cycloalkyl groups include, but are not limited to, bicyclo[l.l.l]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.1.1]hexyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.1]heptyl, bicyclo [3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decyl, norbornenyl, adamantanyl, and the like. A spiro cycloalkyl group refers to a polycyclic cycloalkyl ring system in which one atom is shared between 2 single rings. Illustrative examples of spiro cycloalkyl groups include, but are not limited to, spiro[2.2]pentyl, spiro[2.3]hexyl, spiro[2.4]heptyl, spiro[3.3]heptyl, spiro[3.4]octyl, spiro[3.5]nonyl, spiro[3.6]decyl, spiro[4.4]nonyl, spiro[4.5]decyl, spiro[5.5]undecyl, spiro[5.6]dodecyl, spiro[5.7]tridecyl, and the like. “Cycloalkylene,” alone or as part of another substituent, as used herein, refers to a divalent radical derived from a cycloalkyl group, as defined above. For a cycloalkyl group (or cycloalkylene group) that is bicyclic or polycyclic, one or more rings can be substituted. Unless stated otherwise specifically in the specification, a cycloalkyl group (or cycloalkylene group) is optionally substituted by one or more substituents which independently are: deuterium, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trifluoromethyl, trifluoromethoxy, trimethylsilanyl, pentafluorosulfanyl, -OR', -SR', -OC(O)R', -N(R')2, -C(O)R', -C(O)OR', -OC(O)N(R')2, -C(O)N(R')2, -N(R')C(O)OR', -N(R')C(O)R', -N(R')S(O)tR' (where t is 1 or 2), -N(R')C(O)N(R')2, -N(R')C(NR')N(R')2, -S(O)tR' (where t is 1 or 2), -S(O)tOR' (where t is 1 or 2), -S(O)tN(R')2(where t is 1 or 2), or -PO(OR')2, where each R' is independently hydrogen, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.DB1 / 166057797.1Docket No. 133447-5010-WO

[0035] “Cycloal kylalkyl” refers to a -(cycloal kyl)alkyl radical where cycloalkyl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and alkyl, respectively.

[0036] “Cycloalkyl-heterocycloalkyl” refers to a -(cycloalkyl)heterocycloalkyl radical where cycloalkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and heterocycloalkyl, respectively.

[0037] “Cycloalkyl-heteroaryl” refers to a -(cycloalkyl)heteroaryl radical where cycloalkyl and heteroaryl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and heteroaryl, respectively.

[0038] The term “alkoxy” refers to the group -O-alkyl, including from 1 to 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy, hexoxy, cyclopropyloxy and cyclohexyl oxy. Unless stated otherwise specifically in the specification, the alkyl constituent of an alkoxy group is optionally substituted by one or more substituents which independently are: deuterium, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, cycloal kylalkyl, heterocycloalkyl, heterocycloalkylalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trifluoromethyl, trifluoromethoxy, trimethylsilanyl, pentafluorosulfanyl, -OR', -SR', -OC(O)R', -N(R')2, -C(O)R', -C(O)OR', -OC(O)N(R')2, -C(O)N(R')2, -N(R')C(O)OR', -N(R')C(O)R', -N(R')S(O)tR' (where t is 1 or 2), -N(R')C(O)N(R')2, -N(R')C(NR')N(R')2, -S(O)tR' (where t is 1 or 2), -S(O)tOR' (where t is 1 or 2), -S(O)tN(R')2(where t is 1 or 2), or -PO(OR’)2, where each R' is independently hydrogen, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroaryl alkyl.

[0039] The term “alkoxycarbonyl” refers to a group of the formula (alkoxy)(C=O)- attached through the carbonyl carbon wherein the alkoxy group has the indicated number of carbon atoms. Thus a (Ci-e)alkoxy carbonyl group is an alkoxy group having from 1 to 6 carbon atoms attached through its oxygen to a carbonyl linker. Unless stated otherwise specifically in the DB1 / 166057797.1Docket No. 133447-5010-WOspecification, the alkyl constituent of an alkoxycarbonyl group is optionally substituted by one or more substituents which independently are: deuterium, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trifluoromethyl, trifluoromethoxy, trimethylsilanyl, pentafluorosulfanyl, -OR', -SR', -OC(O)R', -N(R')2, -C(O)R', -C(O)OR', -OC(O)N(R')2, -C(O)N(R')2, -N(R')C(O)OR', -N(R')C(O)R', -N(R')S(O)tR' (where t is 1 or 2), -N(R')C(O)N(R')2, -N(R')C(NR')N(R')2, -S(O)tR' (where t is 1 or 2), -S(O)tOR' (where t is 1 or 2), -S(O)tN(R')2 (where t is 1 or 2), or -PO(OR’)2, where each R' is independently hydrogen, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0040] “Amino” or “amine” refers to a -N(R')2radical group, where each R' is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ring carbon), heterocycloalkylalkyl (bonded through a ring carbon), heteroaryl (bonded through a ring carbon), or heteroarylalkyl (bonded through a ring carbon), unless stated otherwise specifically in the specification. When a -N(R')2 group has two R' substituents other than hydrogen, they may be combined with the nitrogen atom to form a 4-, 5-, 6-, 7-, or 8- membered heterocyclic ring. For example, -N(R')2 is intended to include, but is not limited to, 1- pyrrolidinyl and 4-morpholinyl. Unless stated otherwise specifically in the specification, one or both R' of a -N(R')2group is optionally substituted by one or more substituents which independently are: deuterium, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trifluoromethyl, trifluoromethoxy, trimethylsilanyl, pentafluorosulfanyl, -OR', -SR', -OC(O)R', -N(R')2, -C(O)R', -C(O)OR', -OC(O)N(R')2, -C(O)N(R')2, -N(R')C(O)OR', -N(R')C(O)R', -N(R')S(O)tR' (where t is 1 or 2), -N(R')C(O)N(R')2, -N(R')C(NR')N(R')2, -S(O)tR' (where t is 1 or 2), -S(O)tOR' (where t is 1 or 2), -S(O)tN(R')2(where t is 1 or 2), or -PO(OR')2, where each R' is independently hydrogen, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, fluoroalkyl,DB1 / 166057797.1Docket No. 133447-5010-WOcycloalkyl, cycloalkyl alkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0041] The term “substituted amino” also refers to N-oxides of the group -N(R')2 as described above. N-oxides is prepared by treatment of the corresponding amino group with, for example, hydrogen peroxide or m-chloroperoxybenzoic acid.

[0042] “Amide” or “amido” refers to a chemical moiety with formula -C(O)NR'R" or -NR'C(O)R'', where R' and R" are each independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ring carbon), heterocycloalkylalkyl (bonded through a ring carbon), heteroaryl (bonded through a ring carbon), or heteroarylalkyl (bonded through a ring carbon). The R' and R" of -C(O)NR'R" may optionally be taken together with the nitrogen to which they are attached to form a 4-, 5-, 6-, 7-, or 8- membered heterocyclic ring. Unless stated otherwise specifically in the specification, each R' and R" of a -C(O)NR'R" or -NR'C(O)R" group is optionally substituted by one or more substituents which independently are: deuterium, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trifluoromethyl, trifluoromethoxy, trimethylsilanyl, pentafluorosulfanyl, -OR', -SR', -OC(O)R', -N(R')2, -C(O)R', -C(O)OR', -OC(O)N(R')2, -C(O)N(R')2, -N(R')C(O)OR', -N(R')C(O)R', -N(R')S(O)tR' (where t is 1 or 2), -N(R')C(O)N(R')2, -N(R')C(NR')N(R')2, -S(O)tR' (where t is 1 or 2), -S(O)tOR' (where t is 1 or 2), -S(O)tN(R')2(where t is 1 or 2), or -PO(OR')2, where each R' is independently hydrogen, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0043] An amide may be an amino acid or a peptide molecule attached to a compound disclosed herein, thereby forming a prodrug. The procedures and specific groups to make such amides are known to those of skill in the art and can readily be found in seminal sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3rdEd., John Wiley & Sons, New York, N. Y., 1999, which is incorporated herein by reference in its entirety.DB1 / 166057797.1Docket No. 133447-5010-WO

[0044] Aromatic” or “aryl” or “Ar” refers to an aromatic radical with 6 to 16 ring atoms (e.g., Ce-Ci6 aromatic or Ce-Ci6 aryl), 6 to 14 ring atoms (e.g., Ce-Cw aromatic or Ce-Cw aryl), 6 to 12 ring atoms (e.g., C6-C12 aromatic or C6-C12 aryl), or 6 to 10 ring atoms (e.g., Ce-Cio aromatic or C6-C10aryl), which has at least one cyclic hydrocarbon group with a conjugated pi electron system. Whenever it appears herein, a numerical range such as “6 to 10” refers to each integer in the given range; e.g., “6 to 10 ring atoms” means that the aryl group may consist of 6 ring atoms, 7 ring atoms, etc., up to and including 10 ring atoms. An aryl group can be a single ring (e.g., monocyclic aryl) or multiple rings (e.g., polycyclic aryl) that are fused together (i.e., a fused aryl) or linked covalently (e.g., biphenyl). A fused aryl group refers to multiple rings (e.g., bicyclic, tricyclic or tetracyclic ring system) which share adjacent pairs of ring atoms wherein at least one of the fused rings is an aryl ring. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, fluorenyl, naphthyl, anthracenyl, tolyl, and xylyl. “Arylene,” alone or as part of another substituent, as used herein, refers to a divalent radical derived from an aryl group, as defined above. Divalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals. Divalent radicals derived from univalent polycyclic aromatic hydrocarbon radicals whose names end in “-yl” by removal of one hydrogen atom from the carbon atom with the free valence are named by adding “-idene” to the name of the corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene. For an aryl group (or arylene group) that is bicyclic or polycyclic, one or more rings can be substituted. Unless stated otherwise specifically in the specification, an aryl group (or arylene group) is optionally substituted by one or more substituents which independently are: deuterium, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, hydroxamate, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trifluoromethyl, trifluoromethoxy, trimethylsilanyl, pentafluorosulfanyl, -OR', -SR', -OC(O)R', -N(R')2, -C(O)R', -C(O)OR', -OC(O)N(R')2, -C(O)N(R')2, -N(R')C(O)OR', -N(R')C(O)R', -N(R')S(O)tR' (where t is 1 or 2), -N(R')C(O)N(R')2, -S(O)tR' (where t is 1 or 2), -N(R')C(NR')N(R')2, -S(O)tOR' (where t is 1 or 2), -S(O)tN(R')2 (where t is 1 or 2), or -PO(OR')2, where each R' is independently hydrogen, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, fluoroalkyl,DB1 / 166057797.1Docket No. 133447-5010-WOcycloalkyl, cycloalkyl alkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0045] “Aralkyl” or “arylalkyl” refers to an -(aryl)alkyl radical where aryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl respectively.

[0046] “Ester” refers to a chemical radical of formula -(C=O)OR, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), heteroalkyl (bonded through a chain carbon), and heterocycloalkyl (bonded through a ring carbon). The procedures and specific groups to make esters are known to those of skill in the art and can readily be found in seminal sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3rdEd., John Wiley & Sons, New York, N. Y., 1999, which is incorporated herein by reference in its entirety. Unless stated otherwise specifically in the specification, the R of an ester group (i.e., -(C=O)OR) is optionally substituted by one or more substituents which independently are: deuterium, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trifluoromethyl, trifluoromethoxy, trimethylsilanyl, pentafluorosulfanyl, -OR', -SR', -OC(O)R', -N(R')2, -C(O)R', -C(O)OR', -OC(O)N(R')2, -C(O)N(R')2, -N(R')C(O)OR', -N(R')C(O)R', -N(R')S(O)tR' (where t is 1 or 2), -N(R')C(O)N(R')2, -N(R')C(NR')N(R')2, -S(O)tR' (where t is 1 or 2), -S(O)tOR' (where t is 1 or 2), -S(O)tN(R')2(where t is 1 or 2), or -PO(OR')2, where each R' is independently hydrogen, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0047] “Halo,” “halide,” or, alternatively, “halogen” is intended to mean fluoro (F), chloro (Cl), bromo (Br), or iodo (I). The terms “haloalkyl,” “haloalkenyl,” “haloalkynyl,” and “haloalkoxy” include alkyl, alkenyl, alkynyl and alkoxy groups, respectively, that are substituted with one or more halo groups or with combinations thereof. For example, the terms “fluoroalkyl” and “fluoroalkoxy” include haloalkyl and haloalkoxy groups, respectively, in which the halo is F. Unless stated otherwise specifically in the specification, haloalkyl, haloalkenyl, haloalkynyl, andDB1 / 166057797.1Docket No. 133447-5010-WOhaloalkoxy groups are optionally further substituted by one or more substituents which independently are: deuterium, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, cyano, nitro, oxo, thioxo, trifluoromethyl, trifluoromethoxy, trimethylsilanyl, pentafluorosulfanyl, -OR', -SR', -S(O)tR' (where t is 1 or 2), -OC(O)R', -N(R')2, -C(O)R', -C(O)OR', -OC(O)N(R')2, -C(O)N(R')2, -N(R')C(O)OR', -N(R')C(O)R', -N(R')S(O)tR' (where t is 1 or 2), -N(R')C(O)N(R')2, -N(R')C(NR')N(R')2, -S(O)tOR' (where t is 1 or2), -S(O)tN(R')2(where t is 1 or 2), or -PO(OR')2, where each R' is independently hydrogen, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0048] “Fluoroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, 2,2,2- trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like.

[0049] “Heteroalkyl,” “heteroalkenyl,” and “heteroalkynyl” refer to stable alkyl, alkenyl and alkynyl radicals in which one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or more) skeletal carbon chain atoms are replaced by a heteroatom, / .<?., an atom other than carbon (e.g, oxygen, nitrogen, sulfur, phosphorus or combinations thereof). A numerical range may be given, e.g., 3- to 20-, 3- to 18-, 3- to 16-, 3- to 14-, 3- to 12-, 3- to 10-, 3- to 8-, or 3- to 6-membered heteroalkyl, which refers to the chain length in total (inclusive of the one or more heteroatoms).“Heteroalkylene,” alone or as part of another substituent, as used herein, refers to a divalent radical derived from a heteroalkyl group, as defined above. Unless stated otherwise specifically in the specification, a heteroalkyl, heteroalkenyl, or heteroalkynyl group (or heteroalkylene, heteroalkenylene, or heteroalkynylene group) is optionally substituted by one or more substituents which independently are: deuterium, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trifluoromethyl, trifluoromethoxy, trimethylsilanyl, pentafluorosulfanyl, -OR', -OC(O)R', -C(O)R', -C(O)OR',DB1 / 166057797.1Docket No. 133447-5010-WO-OC(O)N(R')2, -C(O)N(R')2, -N(R')2, -N(R')C(O)OR', -N(R')C(O)R', -N(R')S(O)tR' (where t is 1 or 2), -N(R')C(O)N(R')2, -N(R')C(NR')N(R')2, -SR', -S(O)tR' (where t is 1 or 2), -S(O)tOR' (where t is 1 or 2), -S(O)tN(R')2(where t is 1 or 2), or -PO(OR')2, where each R' is independently hydrogen, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0050] “Heteroalkylaryl” refers to an -(heteroalkyl)aryl radical where heteroalkyl and aryl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and aryl, respectively.

[0051] “Heteroalkylheteroaryl” refers to an -(heteroalkyl)heteroaryl radical where heteroalkyl and heteroaryl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and heteroaryl, respectively.

[0052] “Heteroalkylheterocycloalkyl” refers to an -(heteroalkyl)heterocycloalkyl radical where heteroalkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and heterocycloalkyl, respectively.

[0053] “Heteroalkylcycloalkyl” refers to an -(heteroalkyl)cycloalkyl radical where heteroalkyl and cycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and cycloalkyl, respectively.

[0054] “Heteroaryl” or “heteroaromatic” or “HetAr” refers to a 5- to 18-membered aromatic radical in which 1, 2, 3, 4, 5, or 6 carbon atoms of the aromatic ring system are replaced by a heteroatom independently selected from nitrogen, oxygen, or sulfur atom. Heteroaryl groups can contain from one to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. AN- containing heteroaryl moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom. A numerical range may be given, e.g., 5- to 18-, 5- to 12-, 5- to 10-, 5- to 9-, or 5- to 6-membered heteroaryl, which refers to the total number of ring atomsDB1 / 166057797.1Docket No. 133447-5010-WOin the heteroaryl ring system (inclusive of the one or more heteroatoms). Whenever it appears herein, a numerical range such as “5 to 18” refers to each integer in the given range - e.g., “5 to 18 ring atoms” means that the heteroaryl group may consist of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ring atoms. A heteroaryl group can be a single ring (e.g., monocyclic heteroaryl), or multiple rings (e.g., polycyclic heteroaryl) that are fused together (i.e., a fused heteroaryl) or linked covalently (e.g., bipyridyl). A fused heteroaryl group refers to multiple aromatic rings (e.g., bicyclic, tricyclic or tetracyclic ring system) which share adjacent pairs of ring atoms wherein at least one of the fused aromatic rings is a heteroaromatic ring. The heteroaryl group may be attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryl groups include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, benzofuranyl, isobenzofuranyl, benzo[d]thiazolyl, benzothiadiazolyl, benzothiofuranyl, benzo[6][l,4]oxazinyl, phenanthro[3,4-b]furanyl, benzoxazolyl, benzoisoxazolyl, benzodioxinyl, benzopyranonyl, benzofurazanyl, benzothieno[3,2-b][l]benzothiophenyl, benzothieno[3,2-b]pyrimidinyl, benzotriazolyl, benzo[4,5]imidazo[1,2-a]pyrimidinyl, benzo[4,5]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, dibenzofuranyl, dibenzothiophen-yl, furanyl, furazanyl, furo[3,2-c]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 1,8-naphthyridinyl, 1,6-naphthyridinyl, oxadiazolyl, oxazolyl, oxatriazolyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thienyl. “Heteroarylene,” alone or as part of another substituent, as used herein, refers to a divalent radical derived from a heteroaryl group, as defined above. Divalent radicals derived from univalent heteroaryl radicals whose names end in “-yl” by removal of one hydrogen atom from the atom with the free valence are named by adding “-idene” to the name of the corresponding univalent radical - e.g., a pyridyl group with two points of attachment is a pyridylidene. For a heteroaryl group (or heteroarylene group) that is bicyclic or polycyclic, one or more rings can be substituted. Unless stated otherwise specifically in the specification, a heteroaryl group (or heteroarylene group) is optionally substituted by one or more substituents which independently are: deuterium, alkyl,DB1 / 166057797.1Docket No. 133447-5010-WOalkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, hydroxamate, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trifluoromethyl, trifluoromethoxy, trimethylsilanyl, pentafluorosulfanyl, -OR', -OC(O)R', -C(O)R', -C(O)OR', -OC(O)N(R')2, -C(O)N(R')2, -N(R')2, -N(R')C(O)R', -N(R')C(O)OR', -N(R')S(O)tR' (where t is 1 or 2), -N(R')C(O)N(R')2, -N(R')C(NR')N(R')2, -SR', -S(O)tR' (where t is 1 or 2), -S(O)tOR' (where t is 1 or 2), -S(O)tN(R')2(where t is 1 or 2), or -PO(OR')2, where each R' is independently hydrogen, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0055] Substituted heteroaryl also includes ring systems substituted with one or more oxide (-O-) substituents, such as, for example, pyridinyl N-oxides.

[0056] “Heteroarylalkyl” refers to a -(heteroaryl)alkyl radical where heteroaryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroaryl and alkyl, respectively.

[0057] “Heterocycloalkyl” refers to a stable 3- to f 8-membered non-aromatic ring radical in which f, 2, 3, 4, 5, or 6 carbon atoms of the ring system are replaced by a heteroatom independently selected from nitrogen, oxygen, or sulfur atom. The heterocycloalkyl groups may be completely saturated or partially unsaturated. A numerical range may be given, e.g., 3- to 18-, 3- to 12-, 4- to 11-, 3- to 10-, 3- to 8-, 4- to 7-, 4- to 6-, 3- to 6-, or 3- to 5-membered heterocycloalkyl, which refers to the total number of ring atoms in the heterocycloalkyl ring system (inclusive of the one or more heteroatoms). Whenever it appears herein, a numerical range such as “3 to 18” refers to each integer in the given range - e.g., “3 to 18 ring atoms” means that the heterocycloalkyl group may consist of 3 ring atoms, 4 ring atoms, etc., up to and including 18 ring atoms. A heterocycloalkyl group can be a single ring (e.g., monocyclic heterocycloalkyl) or multiple rings e.g., polycyclic heterocycloalkyl). Polycyclic heterocycloalkyl groups are composed of 2 or more rings (e.g., bicyclic, tricyclic or tetracyclic ring system) and include fused heterocycloalkyl, bridged heterocycloalkyl, and spiro heterocycloalkyl ring systems. “Heterocycloalkyl” also includes bicyclic, tricyclic, or tetracyclic heterocycloalkyl ring systems wherein one ring is either non-aromatic or aromatic, and anotherDB1 / 166057797.1Docket No. 133447-5010-WOring is not aromatic. In other words, for a bicyclic, tricyclic, or tetracyclic heterocycloalkyl ring system, if one ring is aromatic (e.g., aryl or heteroaryl), then the other ring(s) is / are not aromatic. For a bicyclic, tricyclic, or tetracyclic heterocycloalkyl ring system, one or all rings can have one or more heteroatoms. For a bicyclic, tricyclic or tetracyclic heterocycloalkyl ring system, one or all rings can be substituted and the like. The heteroatoms in the heterocycloalkyl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocycloalkyl radical is partially or fully saturated. The heterocycloalkyl may be attached to the rest of the molecule through any atom of the ring(s).

[0058] Examples of such heterocycloalkyl groups include, but are not limited to, azaspiro[2.2]pentyl, diazaspiro[2.2]pentyl, azaspiro[2.3]hexyl, diazaspiro[2.3]hexyl, diazaspiro[3.3]heptyl, azaspiro[3.3]heptyl, azaspiro[2.4]heptyl, diazaspiro[2.4]heptyl, azaspiro[3.4]octyl, diazaspiro[3.4]octyl, azaspiro[3.5]nonyl, diazaspiro[3.5]nonyl, azaspiro[4.4]nonyl, diazaspiro[4.4]nonyl, azaspiro[4.5]decyl, diazaspiro[4.5]decyl, azaspiro[5.5]undecyl, diazaspiro[5.5]undecyl, aziridinyl, azetidine, 1,4-benzodioxanyl, benzo[Z>][l,4]dioxepinyl, benzopyranyl (e.g, chromanyl, isochromanyl), benzofuranonyl, benzodi oxolyl, dioxolanyl, dioxa-tricyclo[3.3.1.03,7]nonyl, thienyl[l,3]dithianyl, 1,4- dihydrobenzotriazinyl, 1,4-dihydrobenzotriazinonyl, decahydroisoquinolyl, dihydroquinazolinonyl, dihydroisoquinolinonyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro- 5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, furanonyl, 5,6,7,8,9,10- hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10- hexahydrocycloocta[d]pyridinyl, imidazolinyl, imidazolidinyl, indolinyl, isothiazolidinyl, isoxazolidinyl, isoxazol-3-one, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, morpholinyl, 1,6- naphthyridinonyl, octahydroindolyl, octahydroisoindolyl, oxabicyclo[3.1.1]heptyl, oxabicyclo[2.2.1]heptyl, oxabicyclo[3.2.1]octyl, oxabicyclo[2.2.2]octyl, 2-oxopiperazinyl, 2- oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxetanyl, oxaspiro[2.2]pentyl, dioxaspiro[2.2]pentyl, oxaspiro[2.3]hexyl, dioxaspiro[2.3]hexyl, oxaspiro[3.3]heptyl, dioxaspiro[3.3]heptyl, oxaspiro[2.4]heptyl, dioxaspiro[2.4]heptyl, oxaspiro[3.4]octyl, dioxaspiro[3.4]octyl, oxaspiro[3.5]nonyl, dioxaspiro[3.5]nonyl, oxaspiro[4.4]nonyl, dioxaspiro[4.4]nonyl, oxaspiro[4.5]decyl, dioxaspiro[4.5]decyl, oxaspiro[5.5]undecyl, dioxaspiro[5.5]undecyl, oxazaspiro[2.2]pentyl, oxazaspiro[2.3]hexyl, oxazaspiro[2.4]heptyl, DB1 / 166057797.1Docket No. 133447-5010-WOoxazaspiro[3.3]heptyl, oxazaspiro[3.4]octyl, oxazaspiro[3.5]nonyl, oxazaspiro[4.4]nonyl, oxazaspiro[4.5]decyl, oxazaspiro[5.5]undecyl, oxathianyl, 2-oxoazepinyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, piperidonyl, pyranyl, pyrrolidinyl, pyrrolidinonyl, pyrazolidinyl, quinuclidinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3- d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5, 6,7,8- tetrahydropyrido[4,5-c]pyridazinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydrobenzazepinyl, tetrahydrobenzazepinonyl, tetrahydrobenzodiazepinyl, tetrahydrobenzodi azepinonyl, tetrahydrobenzoxazepinyl, tetrahydrobenzoxazepinonyl, tetrahydrobenzoxepinyl, tetrahydrobenzoxepinonyl, tetrahydrobenzodi oxepinyl, tetrahydrobenzodioxepinonyl, tetrahydropyranyl, tetrahydrothienyl thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, thiapyranyl, thietanyl, and thiiranyl.

[0059] “Heterocycloalkylene,” alone or as part of another substituent, refers to a divalent radical derived from a heterocycloalkyl. For a heterocycloalkyl group (or heterocycloalkylene group) that is bicyclic or polycyclic, one or more rings can be substituted. Unless stated otherwise specifically in the specification, a heterocycloalkyl group (or heterocycloalkylene group) is optionally substituted by one or more substituents which independently are: deuterium, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, hydroxamate, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trifluoromethyl, trifluoromethoxy, trimethylsilanyl, pentafluorosulfanyl, -OR', -C(O)R', -OC(O)R', -C(O)OR', -0C(0)N(R')2, -C(0)N(R')2, -N(R')2, -N(R')S(0)tR' (where t is 1 or 2), -N(R')C(0)R', -N(R')C(0)0R', -N(R')C(O)N(R')2, -N(R')C(NR')N(R')2, -SR', -S(O)tR' (where t is 1 or 2), -S(O)tOR' (where t is 1 or 2), -S(O)tN(R')2(where t is 1 or 2), or -PO(OR')2, where each R' is independently hydrogen, alkyl, alkylaryl, alkylcycloalkyl, alkylheteroaryl, alkylheterocycloalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0060] “Heterocycloalkylalkyl” refers to a -(heterocycloalkyl)alkyl radical where heterocycloalkyl and alkyl are as disclosed herein and which are optionally substituted by one orDB1 / 166057797.1Docket No. 133447-5010-WOmore of the substituents described as suitable substituents for heterocycloalkyl and alkyl, respectively.

[0061] “Hydroxamate” refers to the -C(O)NRaORamoiety, where each Rais independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0062] “Nitro” refers to the -NO2 radical.

[0063] Oxa” refers to the -O- radical.

[0064] Oxo” refers to the =0 radical.

[0065] “Isomers” are different compounds that have the same molecular formula.“Stereoisomers” are isomers that differ only in the way the atoms are arranged in space - i.e., having a different stereochemical configuration. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1: 1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(±)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn- Ingold-Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon is specified by either (R) or (5). Resolved compounds whose absolute configuration is unknown is designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. Certain of the compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that is defined, in terms of absolute stereochemistry, as (R) or (5). The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active (R)- and ( )-isomers is prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both A and Z geometric isomers.DB1 / 166057797.1Docket No. 133447-5010-WO

[0066] ‘Enantiomeric purity” as used herein refers to the relative amounts, expressed as a percentage, of the presence of a specific enantiomer relative to the other enantiomer. For example, if a compound, which may potentially have an (R)- or an (S)-isomeric configuration, is present as a racemic mixture, the enantiomeric purity is about 50% with respect to either the ( / )- or ( )-isomer. If that compound has one isomeric form predominant over the other, for example, 80% CS')-isomer and 20% (R)-isomer, the enantiomeric purity of the compound with respect to the (S)-isomeric form is 80%. The enantiomeric purity of a compound is determined in a number of ways known in the art, including but not limited to chromatography using a chiral support, polarimetric measurement of the rotation of polarized light, nuclear magnetic resonance spectroscopy using chiral shift reagents which include but are not limited to lanthanide containing chiral complexes or Pirkle’s reagents, or derivatization of a compounds using a chiral compound such as Mosher’s acid followed by chromatography or nuclear magnetic resonance spectroscopy.

[0067] In some embodiments, the enantiomerically enriched composition has a higher potency with respect to therapeutic utility per unit mass than does the racemic mixture of that composition. Enantiomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; preferred enantiomers can be prepared by asymmetric syntheses. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions, Wiley Interscience, New York (1981); E. L. Eliel, Stereochemistry of Carbon Compounds, McGraw-Hill, New York (1962); and E. L. Eliel and S. H. Wilen, Stereochemistry of Organic Compounds, Wiley- Interscience, New York (1994).

[0068] The terms “enantiomerically enriched” and “non-racemic,” as used herein, refer to compositions in which the percent by weight of one enantiomer is greater than the amount of that one enantiomer in a control mixture of the racemic composition (e.g., greater than 1: 1 by weight). For example, an enantiomerically enriched preparation of the (S)-enantiomer, means a preparation of the compound having greater than 50% by weight of the (5)-enantiomer relative to the ( )-enantiomer, such as for example, and without limitation, at least 75% by weight, at least 80% by weight, or the like. In some embodiments, the enrichment is significantly greater than 80% by weight, providing a “substantially enantiomerically enriched” or a “substantially non-DB1 / 166057797.1Docket No. 133447-5010-WOracemic” preparation, which refers to preparations of compositions which have at least 85% by weight of one enantiomer relative to other enantiomer, such as at least 90% by weight, at least 95% by weight, or the like. The terms “enantiomerically pure” or “substantially enantiomerically pure” refer to compositions comprising at least 98% of a single enantiomer and less than 2% of the opposite enantiomer.

[0069] “Moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

[0070] Tautomers” are structurally distinct isomers that interconvert by tautomerization. “Tautomerization” is a form of isomerization and includes prototropic or proton-shift tautomerization, which is considered a subset of acid-base chemistry. “Prototropic tautomerization” or “proton-shift tautomerization” involves the migration of a proton accompanied by changes in bond order, often the interchange of a single bond with an adjacent double bond. Where tautomerization is possible (e.g., in solution), a chemical equilibrium of tautomers is reached. An example of tautomerization is keto-enol tautomerization. A specific example of keto-enol tautomerization is the interconversion of pentane-2, 4-dione and 4- hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers.

[0071] A “leaving group or atom” is any group or atom that will, under selected reaction conditions, cleave from the starting material, thus promoting reaction at a specified site.Examples of such groups, unless otherwise specified, include halogen atoms and mesyloxy, p- nitrobenzensulphonyloxy and tosyloxy groups.

[0072] “Protecting group” is intended to mean a group that selectively blocks one or more reactive sites in a multifunctional compound such that a chemical reaction is carried out selectively on another unprotected reactive site and the group can then be readily removed or deprotected after the selective reaction is complete. A variety of protecting groups are disclosed, for example, in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, New York (1999).DB1 / 166057797.1Docket No. 133447-5010-WO

[0073] Solvate” refers to a compound in physical association with one or more molecules of a pharmaceutically acceptable solvent.

[0074] “Substituted” means that the referenced group may have one or more hydrogen atoms replaced by one or more additional groups, radicals or moieties individually and independently selected from, for example, acyl, alkyl, alkylaryl, cycloalkyl, aralkyl, aryl, carbohydrate, carbonate, deuterium, heteroaryl, heterocycloalkyl, hydroxamate, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, ester, thiocarbonyl, isocyanato, thiocyanato, isothiocyanato, nitro, oxo, perhaloalkyl, perfluoroalkyl, phosphate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, pentafluorosulfanyl, urea, and amino, including mono- and disubstituted amino groups, and protected derivatives thereof. The substituents themselves may be substituted, for example, a cycloalkyl substituent may itself have a halide substituent at one or more of its ring carbons. The term “optionally substituted” means optional substitution with the specified groups, radicals or moieties. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. In certain embodiments, substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds

[0075] “Sulfanyl” refers to groups that include -S-(optionally substituted alkyl), -S- (optionally substituted aryl), -S-(optionally substituted heteroaryl) and -S-(optionally substituted heterocycloalkyl).

[0076] “Pentafluorosulfanyl” refers to the -SF5 radical.DB1 / 166057797.1Docket No. 133447-5010-WO

[0077] “Sulfinyl” refers to groups that include -S(O)-H, -S(O)-(optionally substituted alkyl), -S(O)-(optionally substituted amino), -S(O)-(optionally substituted aryl), -S(O)- (optionally substituted heteroaryl) and -S(O)-(optionally substituted heterocycloalkyl).

[0078] “Sulfonyl” refers to groups that include -S(O2)-H, -S(O2)-(optionally substituted alkyl), -S(O2)-(optionally substituted amino), -S(C>2)-(optionally substituted aryl), -S(C>2)- (optionally substituted heteroaryl), and -S(O2)-(optionally substituted heterocycloalkyl).

[0079] “Sulfonamidyl” or “sulfonamido” refers to a -S(=O)2-NRR radical, where each R is selected independently from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heterocycloalkyl (bonded through a ring carbon). The R groups in -NRR of the -S(=O)2-NRR radical may be taken together with the nitrogen to which it is attached to form a 4-, 5-, 6- or 7-membered ring. A sulfonamido group is optionally substituted by one or more of the substituents described for alkyl, cycloalkyl, aryl, heteroaryl, respectively.

[0080] “Sulfoxyl” refers to a -S(=O)2OH radical.

[0081] “Sulfonate” refers to a -S(=O)2-OR radical, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heterocycloalkyl (bonded through a ring carbon). A sulfonate group is optionally substituted on R by one or more of the substituents described for alkyl, cycloalkyl, aryl, heteroaryl, respectively.

[0082] The term “active pharmaceutical ingredient(s)” include compounds of formula (IA), formula (IIA), formula (IVA), formula (VIA), formula (VIIIA), or formula 1001-1351, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, that inhibit the activity of STAT proteins (e.g., STAT6), as described herein. The term “active pharmaceutical ingredient” may also include other additional compounds that inhibit the activity of STAT proteins (e.g., STAT6).

[0083] Compounds of the disclosure also include crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof. “Crystalline form” and “polymorph” are DB1 / 166057797.1Docket No. 133447-5010-WOintended to include all crystalline and amorphous forms of the compound, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a particular crystalline or amorphous form is referred to.

[0084] As used herein, the terms “administer,” “administration,” or “administering” refer to (1) providing, giving, dosing, and / or prescribing by either a health practitioner or his authorized agent or under his or her direction according to the disclosure; and / or (2) putting into, taking or consuming by the mammal, according to the disclosure.

[0085] The terms “combination,” “pharmaceutical combination,” “co-admini strati on,” “coadministering,” “administered in combination with,” “administering in combination with,” “simultaneous,” and “concurrent,” as used herein, encompass administration of two or more active pharmaceutical ingredients to a subject so that both active pharmaceutical ingredients and / or their metabolites are present in the subject at the same time. Co-administration includes concurrent administration and sequential administration. The simultaneous administration of two or more separate compositions is an example of concurrent co-administration. Another example of concurrent co-administration is the administration of a single composition in which two or more active pharmaceutical ingredients are present. The administration of two or more separate compositions at different times is an example of sequential co-administration.

[0086] Generally, the terms “inhibit,” “inhibition,” “inhibiting,” “inhibitor activity” refer to a change in biological activity for a biological molecule (e.g., a protein, gene, peptide, antibody, and the like), where such change relates to the decrease in biological activity (e.g., decreased activity, antagonism, suppression, deactivation, downregulation, and / or decreased expression) for the biological molecule. It is understood that for purposes of quantification, the terms “activity,” “inhibitory activity,” “biological activity,” “cellular activity,” “STAT protein activity,” “STAT6 protein activity,” and the like, in the context of an inhibitory compound disclosed herein can be quantified in a variety of ways known in the art. As used herein, half maximal inhibitory concentration (IC50) refers to the amount of an inhibitory compound disclosed herein that achieves 50% inhibition of a maximal biological activity or response (e.g., STAT protein activity, STAT6 protein activity, etc.). As used herein, the term “Kd” refers to the dissociation constant, and is reflective of the binding affinity between an inhibitory compoundDB1 / 166057797.1Docket No. 133447-5010-WOdisclosed herein (e.g., a compound according to formula (IA), formula (IIA), formula (IVA), formula (VIA), formula (VIIIA), or formula 1001-1351) and its target (e.g., a STAT protein, or STAT6 protein).

[0087] The term “effective amount” or “therapeutically effective amount” refers to that amount of a compound or combination of compounds as described herein that is sufficient to effect the intended application including, but not limited to, disease treatment. A therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated (e.g., the weight, age and gender of the subject), the severity of the disease condition, the manner of administration, etc., which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that induces a particular response in target cells. The specific dose varies depending on the particular compounds chosen, the dosing regimen to be followed, whether the compound is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which the compound is carried.

[0088] A “therapeutic effect” as that term is used herein, encompasses a therapeutic benefit and / or a prophylactic benefit. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0089] As used herein, the terms “treat,” “treatment,” and / or “treating” may refer to the management of a disease, disorder, or pathological condition, or symptom thereof with the intent to cure, ameliorate, stabilize, and / or control the disease, disorder, pathological condition or symptom thereof. Regarding control of the disease, disorder, or pathological condition more specifically, “control” may include the absence of condition progression, as assessed by the response to the methods recited herein, where such response may be complete (e.g., placing the disease in remission) or partial (e.g., lessening or ameliorating any symptoms associated with the condition). As used herein, the terms “prevent,” “preventing,” and / or “prevention” may refer to reducing the risk of developing a disease, disorder, or pathological condition.

[0090] The term “ / / / vivo" refers to an event that takes place in a subject’s body.DB1 / 166057797.1Docket No. 133447-5010-WO

[0091] The term “ / / ? vitro" refers to an event that takes places outside of a subject’s body. In vitro assays encompass cell-based assays in which cells alive or dead are employed and may also encompass a cell-free assay in which no intact cells are employed.

[0092] The terms “subject” and “patient” are used interchangeably herein to refer to a warm blooded animal such as a mammal, preferably a human, or a human child, which is afflicted with, or has the potential to be afflicted with one or more diseases and / or conditions described herein.

[0093] “Pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and non-human animals without excessive toxicity, irritation, allergic response, or other adverse complications commensurate with a reasonable benefit / risk ratio.

[0094] “Pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” or “physiologically compatible” carrier or carrier medium is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and inert ingredients. The use of such pharmaceutically acceptable carriers or pharmaceutically acceptable excipients for active pharmaceutical ingredients is well known in the art. Except insofar as any conventional pharmaceutically acceptable carrier or pharmaceutically acceptable excipient is incompatible with the active pharmaceutical ingredient(s), its use in the therapeutic compositions of the disclosure is contemplated.

[0095] The term “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions known in the art. Pharmaceutically acceptable acid addition salts is formed with inorganic acids and organic acids. Preferred inorganic acids from which salts is derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid. Preferred organic acids from which salts is derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid.Pharmaceutically acceptable base addition salts is formed with inorganic and organic bases. Inorganic bases from which salts is derived include, for example, sodium, potassium, lithium, DB1 / 166057797.1Docket No. 133447-5010-WOammonium, calcium, magnesium, iron, zinc, copper, manganese and aluminum. Organic bases from which salts is derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins. Specific examples include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts. The term “cocrystal” refers to a molecular complex derived from a number of cocrystal formers known in the art. Unlike a salt, a cocrystal typically does not involve hydrogen transfer between the cocrystal and the drug, and instead involves intermolecular interactions, such as hydrogen bonding, aromatic ring stacking, or dispersive forces, between the cocrystal former and the drug in the crystal structure.

[0096] Acid addition salts include inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric and phosphoric acid, as well as organic acids such as acetic, citric, propionic, tartaric, glutamic, salicylic, oxalic, methanesulfonic, para- toluenesulfonic, succinic, and benzoic acid, and related inorganic and organic acids.

[0097] Base addition salts include those derived from inorganic bases such as ammonium and alkali and alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, as well as salts derived from basic organic compounds such as aliphatic and aromatic amines, aliphatic diamines, hydroxy alkamines, and the like. Such bases useful in preparing the salts of this disclosure thus include ammonium hydroxide, potassium carbonate, sodium bicarbonate, calcium hydroxide, methylamine, diethylamine, ethylenediamine, cyclohexylamine, ethanolamine and the like.

[0098] In addition to pharmaceutically acceptable salts, other salts are included within the scope of this disclosure. They may serve as intermediates in the purification of the compounds, in the preparation of other salts, or in the identification and characterization of the compounds or intermediates.

[0099] The pharmaceutically acceptable salts of compounds of the present disclosure can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, ethyl acetate and the like. Mixtures of such solvates can also be prepared. The source of such solvatesDB1 / 166057797.1Docket No. 133447-5010-WOcan be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent. Such solvates are also within the scope of the present disclosure.

[0100] “Prodrug” is intended to describe a compound that may be converted under physiological conditions or by solvolysis to a biologically active pharmaceutical ingredient described herein. Thus, the term “prodrug” refers to a precursor of a biologically active pharmaceutical ingredient that is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject, but is converted in vivo to an active pharmaceutical ingredient, for example, by hydrolysis. The prodrug compound often offers the advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgaard, H., Design of Prodrugs (1985) (Elsevier, Amsterdam). The term “prodrug” is also intended to include any covalently bonded carriers, which release the active pharmaceutical ingredient in vivo when administered to a subject. Prodrugs of an active pharmaceutical ingredient, as described herein, may be prepared by modifying functional groups present in the active pharmaceutical ingredient in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to yield the active pharmaceutical ingredient. Prodrugs include, for example, compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active pharmaceutical ingredient is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetates, formates and benzoate derivatives of an alcohol, various ester derivatives of a carboxylic acid, or acetamide, formamide and benzamide derivatives of an amine functional group in the active pharmaceutical ingredient.

[0101] Unless otherwise stated, the chemical structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds where one or more hydrogen atoms is replaced by deuterium or tritium, or wherein one or more carbon atoms is replaced by13C- or14C-enriched carbons, are within the scope of this disclosure.

[0102] As will be apparent to anyone skilled in the art, the compounds of the present disclosure may have one or more chiral centers, and in that case, exist in various stereoisomeric forms. The compounds of the present disclosure encompass all such optical isomers, diastereomers and enantiomers. The compounds are normally prepared as a racemic mixture orDB1 / 166057797.1Docket No. 133447-5010-WOracemate and can conveniently be used as such, but individual enantiomers can be isolated or synthesized by conventional techniques if so desired. Such racemates and individual enantiomers and mixtures thereof form part of the present disclosure.

[0103] It is well known in the art how to prepare and isolate such optically active forms from a mixture of enantiomers. Specific stereoisomers can be prepared by stereospecific synthesis using enantiomerically pure or enantiomerically enriched starting materials. The specific stereoisomers of either starting materials or products can be resolved and recovered by techniques known in the art, such as resolution of racemic forms, normal, reverse-phase, and chiral chromatography, recrystallization, enzymatic resolution, or fractional recrystallization of addition salts formed by reagents used for that purpose. Useful methods of resolving and recovering specific stereoisomers described in Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds; Wiley: New York, 1994, and Jacques, J, et al. Enantiomers, Racemates, and Resolutions; Wiley: New York, 1981, each incorporated by reference herein in their entireties.

[0104] For the avoidance of doubt, it is intended herein that particular features (for example integers, characteristics, values, uses, diseases, formulae, compounds or groups) described in conjunction with a particular aspect, embodiment or example of the disclosure are to be understood as applicable to any other aspect, embodiment or example described herein unless incompatible therewith. Thus such features may be used where appropriate in conjunction with any of the definition, claims or embodiments defined herein. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of the features and / or steps are mutually exclusive. The disclosure is not restricted to any details of any disclosed embodiments. The disclosure extends to any novel one, or novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.DB1 / 166057797.1Docket No. 133447-5010-WOCompounds

[0105] In aspects, the disclosure relates to a compound of formula (IA), or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof:(R5)n (IA), wherein in formula (IA):Ai is N or CR1;A2 is N or CR2;A3 is N or CR3;R1, R2, and R3are each independently selected from H, deuterium, halide, -CN, -ORa, -N(Ra)2, -NO2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 6-membered heterocycloalkyl;ring A is aryl or heteroaryl;ring B is selected from aryl, cycloalkyl, heteroaryl, and heterocycloalkyl;R4and R5are independently at each occurrence selected from deuterium, halide, -CN, trimethylsilanyl, oxo, -ORa, -SRa, -S(O)tRa, -OC(O)Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, - C(O)N(Ra)2, -NO2, -OC(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, - N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -C(O)N(Ra)S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, - S(O)tN(Ra)C(O)Ra, -P(O)(ORa)2, optionally substituted Ci-Ce alkyl, optionally substituted C2-Ce alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C8 cycloalkyl, optionally substituted3- to 8-membered heteroalkyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocycloalkyl;DB1 / 166057797.1Docket No. 133447-5010-WOm and n are each independently selected from 0, 1, 2, 3, and 4;t is 1 or 2;R6and R6' are each independently selected from H, deuterium, halide, -CN, -ORa, - N(Ra)2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted C6-C12 aryl, optionally substituted C3-C8 cycloalkyl, optionally substituted3- to 8-membered heteroalkyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocycloalkyl; or R6and R6are taken together to form =C(Rb)2;Rais independently at each occurrence selected from H, deuterium, -OH, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl; or two Ragroups are taken together with the atom to which they are attached to form optionally substituted 5- to 6-membered heteroaryl or optionally substituted3- to 6-membered heterocycloalkyl; andRbis independently at each occurrence selected from H, deuterium, halide, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heteroalkyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted3- to 12-membered heterocycloalkyl.

[0106] In some embodiments, R1, R2, and R3are each independently selected from H, halide, -CN, -ORa, -N(Ra)2, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 haloalkyl, optionally substituted phenyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 6-membered heterocycloalkyl.

[0107] In some embodiments, R1, R2, and R3are each independently selected from H, halide, -ORa, -N(Ra)2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 haloalkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl,DB1 / 166057797.1Docket No. 133447-5010-WOoptionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 5-membered heterocycloalkyl.

[0108] In some embodiments, ring A is phenyl or 5- to 6-membered heteroaryl.

[0109] In some embodiments, ring B is selected from aryl, heteroaryl, and heterocycloalkyl.

[0110] In some embodiments, R4is independently at each occurrence selected from halide, - CN, oxo, -ORa, -SRa, -S(O)tRa, -OC(O)Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -NO2, - N(Ra)C(0)Ra, -N(Ra)S(O)tRa, -C(O)N(Ra)S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, -S(O N(Ra)C(O)Ra, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted C6-C10 aryl, optionally substituted C3-C8cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocycloalkyl.

[0111] In some embodiments, R5is independently at each occurrence selected from halide, - CN, trimethylsilanyl, oxo, -ORa, -SRa, -S(O)tRa, -OC(O)Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, - C(O)N(Ra)2, -NO2, -OC(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, - N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -C(O)N(Ra)S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, - S(O)tN(Ra)C(O)Ra, -P(O)(ORa)2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted C6-C10 aryl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocycloalkyl.

[0112] In some embodiments, m is 1, 2, 3, or 4.

[0113] In some embodiments, n is 1, 2, 3, or 4.

[0114] In some embodiments, R6and R6are each independently selected from H, deuterium, halide, -CN, -ORa, -N(Ra)2, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl; or R6and R6are taken together to form =C(Rb)2.DB1 / 166057797.1Docket No. 133447-5010-WO

[0115] In some embodiments, R6and R6'are each independently selected from H, deuterium, halide, -CN, -ORa, -N(Ra)2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 haloalkyl, optionally substituted phenyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 8-membered heterocycloalkyl; or R6and R6'are taken together to form =C(Rb)2.

[0116] In some embodiments, Rais independently at each occurrence selected from H, -OH, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl; or two Ragroups are taken together with the atom to which they are attached to form optionally substituted 5- to 6-membered heteroaryl or optionally substituted 3- to 6-membered heterocycloalkyl.

[0117] In some embodiments, the compound of formula (IA), or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, is a compound having a structure according to formula (IIA):B,5-'n (IIA), wherein in formula (IIA):Ai is N or CR1;A2is N or CR2;A3 is N or CR3;R1, R2, and R3are each independently selected from H, halide, -ORa, -N(Ra)2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 haloalkyl, optionally substituted C3-C5DB1 / 166057797.1Docket No. 133447-5010-WOcycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted5- to 6-membered heteroaryl, and optionally substituted 3- to 5-membered heterocycloalkyl;A4 is N or CR41;A5 is N or CR51;Yi and Y2 are each independently selected from N and CRY; or Yi is absent, and Y2 is selected from NRb, O, and S;R41, R51, and RYare each independently selected from H, halide, -CN, -ORa, -S(O)tRb, - OC(O)Rb, -N(Rb)2, -C(O)Rb, -C(O)N(Rb)2, -N(Ra)C(O)Rb, -S(O)tN(Rb)2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 haloalkyl, optionally substituted C3-C4 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, and optionally substituted3- to 4-membered heterocycloalkyl;ring B is selected from phenyl, 5- to 6-membered heteroaryl, and 3- to 10-membered heterocycloalkyl;R4is selected from -S(O)tRa, -OC(O)Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)Ra, -N(Ra)S(O)tRa, -C(O)N(Ra)S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, -S(O)tN(Ra)C(O)Ra, substituted C1-C4 alkyl, substituted C6-C10aryl, substituted C3-C8 cycloalkyl, substituted 5- to 10-membered heteroaryl, and substituted 3- to 10-membered heterocycloalkyl;R5is independently at each occurrence selected from halide, -CN, oxo, -ORa, -SRa, - S(O)tRa, -OC(O)Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -NO2, -OC(O)N(Ra)2, - N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, - C(O)N(Ra)S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, -S(O)tN(Ra)C(O)Ra, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl;n is 1, 2, or 3;t is 1 or 2;R6and R6'are each independently selected from H, deuterium, halide, -CN, -ORa, - N(Ra)2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 haloalkyl, optionally substituted phenyl, optionally substituted C3-C6 cycloalkyl, optionally substituted3- to 6-membered heteroalkyl, optionally substituted 5- to 6-membered heteroaryl, andDB1 / 166057797.1Docket No. 133447-5010-WOoptionally substituted 3- to 8-membered heterocycloalkyl; or R6and R6'are taken together to form =C(Rb)2;Rais independently at each occurrence selected from H, -OH, optionally substituted Ci- C4 alkyl, optionally substituted C1-C4 haloalkyl, optionally substituted phenyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 6-membered heterocycloalkyl; or two Ragroups are taken together with the atom to which they are attached to form optionally substituted 5- to 6-membered heteroaryl or optionally substituted 3- to 6-membered heterocycloalkyl; andRbis independently at each occurrence selected from H, deuterium, halide, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 haloalkyl, optionally substituted phenyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 6-membered heterocycloalkyl.

[0118] In some embodiments, R4is selected from -S(O)tRa, -OC(O)Ra, -N(Ra)2, -C(O)Ra, - C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa, -C(O)N(Ra)S(O)tRa, -S(O)tORa, - S(O)tN(Ra)2, -S(O)tN(Ra)C(O)Ra, substituted C1-C4 alkyl, substituted C6-C10 aryl, substituted C3- Cs cycloalkyl, substituted 5- to 10-membered heteroaryl, and substituted 3- to 10-membered heterocycloalkyl; wherein at least one atom of alkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is substituted with an oxo group, and the alkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl are optionally further substituted with one or more Rcgroups; and Rcis independently at each occurrence selected from halide, -CN, -ORa, -SRa, -S(O)tRa, -OC(O)Ra, - N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -NO2, -OC(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -C(O)N(Ra)S(O)tRa, -S(O)tORa, - S(O)tN(Ra)2, -S(O)tN(Ra)C(O)Ra, -P(O)(ORa)2, optionally substituted C1-C6alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C6-C10 aryl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heteroalkyl, optionally substituted5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl.

[0119] In some embodiments, R4is selected from -S(O)tRa, -N(Ra)2, -C(O)Ra, -C(O)N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa, -S(O)tN(Ra)2, -S(O)tN(Ra)C(O)Ra, substituted phenyl, substitutedDB1 / 166057797.1Docket No. 133447-5010-WOC4-C8cycloalkyl, substituted 5- to 6-membered heteroaryl, and substituted 4- to 8-membered heterocycloalkyl.

[0120] In some embodiments, R4is selected from -S(O)tRa, -N(Ra)2, -C(O)Ra, -C(O)N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa, -S(O)tN(Ra)2, -S(O)tN(Ra)C(O)Ra, substituted phenyl, substituted C4-Cs cycloalkyl, substituted 5- to 6-membered heteroaryl, and substituted 4- to 8-membered heterocycloalkyl; wherein at least one atom of phenyl, cycloalkyl, heteroaryl, and heterocycloalkyl is substituted with an oxo group, and the phenyl, cycloalkyl, heteroaryl, and heterocycloalkyl are optionally further substituted with one, two, or three Rcgroups; and Rcis independently at each occurrence selected from halide, -CN, -ORa, -SRa, -S(O)tRa, -OC(O)Ra, - N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -NO2, -OC(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -C(O)N(Ra)S(O)tRa, -S(O)tORa, - S(O)tN(Ra)2, -S(O)tN(Ra)C(O)Ra-P(O)(ORa)2, optionally substituted C1-C6alkyl, optionally substituted C1-C6haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heteroalkyl, optionally substituted5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl.

[0121] In some embodiments, R4is selected from -C(O)Ra, -C(O)N(Ra)2, -N(Ra)C(O)Ra, -S(O)tN(Ra)2, C4-C8 cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 8-membered heterocycloalkyl; wherein at least one ring atom of cycloalkyl, heteroaryl, and heterocycloalkyl is substituted with an oxo group, and the cycloalkyl, heteroaryl, and heterocycloalkyl are optionally further substituted with one, two, or three Rcgroups; and Rcis independently at each occurrence selected from halide, -CN, -ORa, -N(Ra)2, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl.

[0122] In some embodiments, R4is a moiety of formula (IIIA):wherein in formula (IIIA):DB1 / 166057797.1Docket No. 133447-5010-WO- is a single bond or a double bond;Ae is selected from N, C, and CH;X is selected from NRdor N; C(Rd)2 or CRd; O; and S;Zi, Z2, and Z3 are each independently selected from NRd, N, C(Rd)2, CRd, C(O), O, and S; p and q are each independently selected from 0 and 1; andRdis independently at each occurrence selected from H, halide, -CN, -ORa, -N(Ra)2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 haloalkyl, optionally substituted phenyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 6-membered heterocycloalkyl.

[0123] In some embodiments, the compound of formula (IA) and / or formula (IIA), or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, is a compound having a structure according to formula (IVA):wherein in formula (IVA):ring B is selected from phenyl, pyridine, pyrazine, pyrimidine, pyridazine, triazine, tetrazine.

[0124] In some embodiments, the compound of formula (IA) and / or formula (IIA), or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, is a compound having a structure according to formula (IVA), wherein:Ai is N or CR1;A2 is N or CR2;A3 is N or CR3;DB1 / 166057797.1Docket No. 133447-5010-WOR1, R2, and R3are each independently selected from H, halide, -ORa, -N(Ra)2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 haloalkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted5- to 6-membered heteroaryl, and optionally substituted 3- to 5-membered heterocycloalkyl;A4 is N or CR41;A5 is N or CR51;Yi and Y2 are each independently selected from N and CRY;R41, R51, and RYare each independently selected from H, halide, -CN, -ORa, -S(O)tRb, - OC(O)Rb, -N(Rb)2, -C(O)Rb, -C(O)N(Rb)2, -N(Ra)C(O)Rb, -S(O)tN(Rb)2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 haloalkyl, optionally substituted C3-C4 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, and optionally substituted3- to 4-membered heterocycloalkyl;ring B is selected from phenyl, pyridine, pyrazine, pyrimidine, pyridazine, triazine, tetrazine;- is a single bond or a double bond;A₆ is selected from N, C, and CH;X is selected from NRdor N; C(Rd)2 or CRd; O; and S;Zi, Z2, and Z3 are each independently selected from NRd, N, C(Rd)2, CRd, C(O), O, and S; p and q are each independently selected from 0 and 1;R5is independently at each occurrence selected from halide, -CN, oxo, -ORa, -SRa, - S(O)tRa, -OC(O)Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -NO2, -OC(O)N(Ra)2, - N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, - C(O)N(Ra)S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, -S(O)tN(Ra)C(O)Ra, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl;n is 1, 2, or 3;t is 1 or 2;R6and R6'are each independently selected from H, deuterium, halide, -CN, -ORa, -N(Ra)2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 haloalkyl, optionallyDB1 / 166057797.1Docket No. 133447-5010-WOsubstituted phenyl, optionally substituted C3-C6 cycloalkyl, optionally substituted3- to 6-membered heteroalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 8-membered heterocycloalkyl; or R6and R6'are taken together to form =C(Rb)2;Rais independently at each occurrence selected from H, -OH, optionally substituted Ci- C4 alkyl, optionally substituted C1-C4 haloalkyl, optionally substituted phenyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 6-membered heterocycloalkyl; or two Ragroups are taken together with the atom to which they are attached to form optionally substituted 5- to 6-membered heteroaryl or optionally substituted 3- to 6-membered heterocycloalkyl;Rbis independently at each occurrence selected from H, deuterium, halide, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 haloalkyl, optionally substituted phenyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 6-membered heterocycloalkyl; andRdis independently at each occurrence selected from H, halide, -CN, -ORa, -N(Ra)2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 haloalkyl, optionally substituted phenyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 6-membered heterocycloalkyl.

[0125] In some embodiments of formula (IIA) and / or formula (IVA), A4 is CR41.

[0126] In some embodiments of formula (IIA) and / or formula (IVA), As is CR51.

[0127] In some embodiments of formula (IIA) and / or formula (IVA), Yi is CR'.

[0128] In some embodiments of formula (IIA) and / or formula (IVA), Y2is CRY.

[0129] In some embodiments of formula (IIA) and / or formula (IVA), A4 is CR41; As is CR51;Yi is CRY; and Y2is CRY.

[0130] In some embodiments of formula (IIA) and / or formula (IVA), R41, R51, and RYare each independently selected from H, halide, -CN, -ORa', -S(O)2Rb', -N(Rb')2, -C(O)Rb', - C(O)N(Rb')2, -N(Ra')C(O)Rb', and optionally substituted C1-C3 alkyl;DB1 / 166057797.1Docket No. 133447-5010-WORais independently at each occurrence selected from H, optionally substituted C1-C3 alkyl, optionally substituted C3-C4 cycloalkyl, and optionally substituted 3- to 4-membered heterocycloalkyl; andRbis independently at each occurrence selected from H, deuterium, optionally substituted C1-C3 alkyl, optionally substituted C3-C4 cycloalkyl, and optionally substituted 3- to 4-membered heterocycloalkyl.

[0131] In some embodiments of formula (IIA) and / or formula (IVA), R41, R51, and RYare each independently selected from H, halide, -CN, -OCH3, -S(O)2CH3, -C(O)CH3, and optionally substituted C1-C3 alkyl. In some embodiments of formula (IIA) and / or formula (IVA), R41, R51, and RYare each independently selected from H, F, Cl, Br, -CN, -OCH3, -S(O)2CH3, -C(O)CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH(CH3)2, and -CH2N(CH3)2.[00132J In some embodiments of formula (1A), ring A is aryl, fused aryl, 5- to 6-membered heteroaryl, or fused heteroaryl. In some embodiments of formula (IA), ring A is selected from phenyl, 1 -carboxamide- 1,2,3,4-tetrahy droisoquinolin-6-yl, 2-m ethyl- 1 -oxo- 1,2,4, 5-tetrahydro- [l,2,4]triazolo[4,3-a]quinolin-7-yl, or pyridinyl. In some embodiments of formula (IA), ring A isHN. In some embodiments of formula (IA), ring A is In some embodiments of formula (IA), ring A is phenyl. In some embodiments of formula (IA), ring A is pyridinyl.

[0133] In some embodiments of formula (IA), formula (IIA), and / or formula (IVA), ring B is selected from phenyl, pyridine, pyrazine, pyrimidine, and pyridazine. In some embodiments of formula (IA), formula (IIA), and / or formula (IVA), ring B is selected from phenyl, pyridine, pyrazine, and pyrimidine. In some embodiments of formula (IA), formula (IIA), and / or formula (IVA), ring B is selected from phenyl, pyridine, and pyrazine. In some embodiments of formula (IA), formula (IIA), and / or formula (IVA), ring B is selected from phenyl and pyridine. In some embodiments of formula (IA), formula (IIA), and / or formula (IVA), ring B is phenyl. In some embodiments of formula (IA), formula (IIA), and / or formula (IVA), ring B is pyridine.DB1 / 166057797.1Docket No. 133447-5010-WO

[0134] In some embodiments of formula (IA), formula (IIA), and / or formula (IVA), Ai is N. In some embodiments of formula (IA), formula (IIA), and / or formula (IVA), Ai is CR1.

[0135] In some embodiments of formula (IA), formula (IIA), and / or formula (IVA), R1is selected from H, halide, -CN, -ORla, -N(Rla)2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 haloalkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 5-membered heterocycloalkyl; andRlais selected from H, optionally substituted C1-C3 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 5-membered heterocycloalkyl.

[0136] In some embodiments of formula (IA), formula (IIA), and / or formula (IVA), A2 is N. In some embodiments of formula (IA), formula (IIA), and / or formula (IVA), A2 is CR2.

[0137] In some embodiments of formula (IA), formula (IIA), and / or formula (IVA), R2is selected from H, halide, -CN, -OR2a, -N(R2a)2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 haloalkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 5-membered heterocycloalkyl; andR2ais selected from H, optionally substituted C1-C3 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 5-membered heterocycloalkyl.

[0138] In some embodiments of formula (I A), formula (IIA), and / or formula (IVA), A3 is N. In some embodiments of formula (IA), formula (IIA), and / or formula (IVA), A3 is CR3.

[0139] In some embodiments of formula (IA), formula (IIA), and / or formula (IVA), R3is selected from H, halide, -CN, -OR3a, -N(R3a)2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 haloalkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 5-membered heterocycloalkyl; andDB1 / 166057797.1Docket No. 133447-5010-WOR3ais selected from H, optionally substituted C1-C3 alkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 5-membered heterocycloalkyl.

[0140] In some embodiments of formula (IA), formula (IIA), and / or formula (IVA), R1is selected from H, halide, and optionally substituted C1-C3 alkyl. In some embodiments of formula (IA), formula (IIA), and / or formula (IVA), R2is selected from H, halide, -CN, -OH, - OCH3, -NH2, -N(CH3)2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 haloalkyl, optionally substituted C3-C4 cycloalkyl, and optionally substituted 3- to 4-membered heterocycloalkyl. In some embodiments of formula (IA), formula (IIA), and / or formula (IVA), R3is selected from H, halide, and optionally substituted C1-C3 alkyl.

[0141] In some embodiments of formula (IA), and / or formula (IIA), R4is selected from - C(O)N(R4a)2, -N(R4a)C(O)R4a, -S(O)2N(R4a)2, C4-C8cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 8-membered heterocycloalkyl;wherein at least one ring atom of cycloalkyl, heteroaryl, and heterocycloalkyl is substituted with an oxo group, and the cycloalkyl, heteroaryl, and heterocycloalkyl are optionally further substituted with one, two, or three Rcgroups;Rcis independently at each occurrence selected from halide, -CN, -OR4a, -N(R4a)2, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl; andR4ais independently at each occurrence selected from H, -OH, optionally substituted C1- C4 alkyl, optionally substituted phenyl, optionally substituted C3-C8cycloalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl; or two Ragroups are taken together with the atom to which they are attached to form optionally substituted 5- to 6-membered heteroaryl or optionally substituted3- to 6-membered heterocycloalkyl.

[0142] In some embodiments of formula (IA), and / or formula (IIA), R4is selected from C4- C8cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 8-membered heterocycloalkyl;DB1 / 166057797.1Docket No. 133447-5010-WOwherein at least one ring atom of cycloalkyl, heteroaryl, and heterocycloalkyl is substituted with an oxo group, and the cycloalkyl, heteroaryl, and heterocycloalkyl are optionally further substituted with one, two, or three Rcgroups;Rcis independently at each occurrence selected from halide, -CN, -OR4a, -N(R4a)2, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl; andR4ais independently at each occurrence selected from H, -OH, optionally substituted Ci- C4 alkyl, optionally substituted phenyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl.

[0143] In some embodiments of formula (IIIA) and / or formula (IVA), Ae is N.

[0144] In some embodiments of formula (IIIA) and / or formula (IVA), X is NRd. In some embodiments of formula (IIIA) and / or formula (IVA), Zi is selected from NRd, N, C(Rd)2, CRd, and C(O). In some embodiments of formula (IIIA) and / or formula (IVA), Z2 is selected from NRd, N, C(Rd)2, CRd, and C(O). In some embodiments of formula (IIIA) and / or formula (IVA), Z3 is selected from C(Rd)2, CRd, and C(O).

[0145] In some embodiments of formula (IIIA) and / or formula (IVA), p is 1. In some embodiments of formula (IIIA) and / or formula (IVA), p is 0. In some embodiments of formula (IIIA) and / or formula (IVA), q is 1. In some embodiments of formula (IIIA) and / or formula (IVA), q is 0. In some embodiments of formula (IIIA) and / or formula (IVA), p is 0 and q is 0. In some embodiments of formula (IIIA) and / or formula (IVA), p is 1 and q is 1. In some embodiments of formula (IIIA) and / or formula (IVA), p is 1 and q is 0. In some embodiments of formula (IIIA) and / or formula (IVA), p is 0 and q is 1.

[0146] In some embodiments of formula (IIIA) and / or formula (IVA), Rdis independently at each occurrence selected from H, halide, -CN, -ORd, -N(Rd)2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 haloalkyl, optionally substituted phenyl, optionally substituted C3- Ce cycloalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 6-membered heterocycloalkyl; andDB1 / 166057797.1Docket No. 133447-5010-WORdis independently at each occurrence selected from H, optionally substituted C1-C4 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl.

[0147] In some embodiments of formula (IA), formula (IIA), and / or formula (IIIA), R4is a moiety of formula (VA):(VA),wherein in formula (VA):Rdis independently at each occurrence selected from H, halide, -ORd, optionally substituted C1-C3 alkyl, -CD3, C1-C2 haloalkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 5-membered heterocycloalkyl; andRd’ is independently at each occurrence selected from H, optionally substituted C1-C3 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl.

[0148] In some embodiments, the compound of formula (IA), formula (IIA), and / or formula (IVA), or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, is a compound having a structure according to formula (VIA):R51R41R2N \I N RN^ / N(R5)n (VIA), wherein in formula (VIA):DB1 / 166057797.1Docket No. 133447-5010-WOR1is selected from H, halide, and optionally substituted C1-C3 alkyl;R2is selected from H, halide, -CN, -OH, -OCH3, -NH2, -N(CH3)2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 haloalkyl, optionally substituted C3-C4 cycloalkyl, and optionally substituted 3- to 4-membered heterocycloalkyl;R3is selected from H, halide, and optionally substituted C1-C3 alkyl;R41is selected from H, F, Cl, Br, -CN, -OCH3, -S(O)2CH3, -C(O)CH3, -CH3, -CH2CH3, - CH2CH2CH3, -CH2CH(CH3)2, and -CH2N(CH3)2;R51is selected from H, F, Cl, Br, -CN, -OCH3, -S(O)2CH3, -C(O)CH3, -CH3, -CH2CH3, - CH2CH2CH3, -CH2CH(CH3)2, and -CH2N(CH3)2;RYare each independently selected from H, F, Cl, Br, -CN, -OCH3, -S(O)2CH3, - C(O)CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH(CH3)2, and -CH2N(CH3)2;Rdis independently at each occurrence selected from H, halide, -ORd, optionally substituted Ci-C3alkyl, -CD3, C1-C2haloalkyl, optionally substituted C3-C8cycloalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 5-membered heterocycloalkyl;Rdis independently at each occurrence selected from H, optionally substituted C1-C3 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl;R5is independently at each occurrence selected from halide, -CN, oxo, -ORa, -SRa, - S(O)tRa, -OC(O)Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -NO2, -OC(O)N(Ra)2, - N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, - C(O)N(Ra)S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, -S(O)tN(Ra)C(O)Ra, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-Cs cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl;n is 1, 2, or 3;t is 1 or 2;R6and R6are each independently selected from H, deuterium, halide, -CN, -ORa, -N(Ra)2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 haloalkyl, optionally substituted phenyl, optionally substituted C3-C6cycloalkyl, optionally substitutedDB1 / 166057797.1Docket No. 133447-5010-WO3- to 6-membered heteroalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 8-membered heterocycloalkyl; or R6and R6are taken together to form =C(Rb)2; andRais independently at each occurrence selected from H, -OH, optionally substituted Ci- C4 alkyl, optionally substituted C1-C4 haloalkyl, optionally substituted phenyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 6-membered heterocycloalkyl; or two Ragroups are taken together with the atom to which they are attached to form optionally substituted 5- to 6-membered heteroaryl or optionally substituted 3- to 6-membered heterocycloalkyl.

[0149] In some embodiments of formula (IA), formula (IIA), formula (IVA), and / or formula (VIA), R1is H or halide. In some embodiments of formula (IA), formula (IIA), formula (IVA), and / or formula (VIA), R1is H.

[0150] In some embodiments of formula (IA), formula (IIA), formula (IVA), and / or formula (VIA), R2is selected from H, Cl, Br, F, -CN, -OCH3, -N(CH3)2, -CH3, -CF3, cyclopropyl, and oxetanyl.

[0151] In some embodiments of formula (IA), formula (IIA), formula (IVA), and / or formula (VIA), R3is H or halide. In some embodiments of formula (IA), formula (IIA), and / or formula (IVA), R3is H.

[0152] In some embodiments of formula (IA), formula (IIA), formula (IVA), and / or formula (VIA), R? is independently at each occurrence selected from halide, -CN, -OR5a, -N(R5a)2, -C(O)Ra, -C(O)N(R5a)2, -N(R5a)C(O)R5a, -N(R5a)C(O)N(R5a)2, -N(R5a)S(O)2R5a, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 haloalkyl, optionally substituted phenyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl; andR5ais independently at each occurrence selected from H, -OH, optionally substituted Ci- C3 alkyl, optionally substituted C1-C3 haloalkyl, optionally substituted phenyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 6-membered heterocycloalkyl; or two R5agroups are taken together with the atom to which they are attached to form optionally substituted 5- to 6-membered heteroaryl or optionally substituted 3- to 6-membered heterocycloalkyl.DB1 / 166057797.1Docket No. 133447-5010-WO

[0153] In some embodiments of formula (IA), formula (IIA), formula (IVA), and / or formula (VIA), R5is independently at each occurrence selected from halide, -CN,-C(O)N(R5a)2, - N(R5a)C(O)R5a, -N(R5a)C(O)N(R5a)2, -N(R5a)S(O)2R5a, optionally substituted C1-C3 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 8-membered heterocycloalkyl; andR3ais independently at each occurrence selected from H, -OH, optionally substituted Ci- C3 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 6-membered heterocycloalkyl; or two R5agroups are taken together with the atom to which they are attached to form optionally substituted3- to 6-membered heterocycloalkyl.

[0154] In some embodiments of formula (IA), formula (IIA), formula (IVA), and / or formula (VIA), R3is independently at each occurrence selected from F, -CN, -CH3, -C(O)N(R3a)2, optionally substituted C3-C8 cycloalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 8-membered heterocycloalkyl; andR5ais independently at each occurrence selected from H, optionally substituted C1-C3 alkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted3- to 6-membered heterocycloalkyl.

[0155] In some embodiments of formula (IA), formula (IIA), formula (IVA), and / or formula (VIA), R6and R6are each independently selected from H, deuterium, halide, -CN, -OR6a, - NHR6a, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 haloalkyl, optionally substituted phenyl, optionally substituted C3-C6 cycloalkyl, optionally substituted5- to 6-membered heteroaryl, and optionally substituted 3- to 8-membered heterocycloalkyl; or R6and R6are taken together to form =C(R6b)2;R6ais independently at each occurrence selected from H, optionally substituted C1-C3 alkyl, optionally substituted C1-C4 haloalkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocycloalkyl; andR6bis independently at each occurrence selected from H, deuterium, halide, C1-C3 alkyl, and C1-C3 haloalkyl.

[0156] In some embodiments of formula (VA) and / or formula (VIA), Rdis independently at each occurrence selected from H, halide, -ORd, optionally substituted C1-C3 alkyl, -CD3, C1-C2DB1 / 166057797.1Docket No. 133447-5010-WOhaloalkyl, optionally substituted C3-C5 cycloalkyl, and optionally substituted 3- to 5-membered heterocycloalkyl; andRd’ is independently at each occurrence selected from H, optionally substituted C1-C3 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl;wherein each alkyl, cycloalkyl, heteroaryl, and heterocycloalkyl of Rdand Rdis optionally substituted with 1, 2, or 3 groups independently selected from:C1-C3 alkyl; -CN; -OH; -OCH3; -NH2; -N(CH3)2; oxo; C3-C8 cycloalkyl optionally substituted with 1, 2, or 3 independently selected groups of -CH3, -CN, and oxo; and 3- to 10-membered heterocycloalkyl optionally substituted with 1, 2, or 3 independently selected groups of -CH3, -CN, and oxo.

[0157] In some embodiments of formula (VA) and / or formula (VIA), Rdis independently at each occurrence selected from H, Cl, -CHF2, -CH3, -CH2CH3, -CH2OCH3, -CH2OH, - CH2N(CH3)2, -CH2-azetidine, -CH(CH3)2, cyclopropyl, -CD3, and oxetane.

[0158] In some embodiments of formula (IA), formula (IIA), formula (IIIA), and / or formula (VA), R4is a moiety of formula (VIIA):°'~'Rd(VIIA),wherein in formula (VIIA):Rdis selected from H, optionally substituted C1-C3 alkyl, -CD3, optionally substituted C3- C4 cycloalkyl, and optionally substituted 3- to 4-membered heterocycloalkyl; andRd'is selected from H, optionally substituted C1-C3 alkyl, optionally substituted C3-C8 cycloalkyl, and optionally substituted 3- to 10-membered heterocycloalkyl.DB1 / 166057797.1Docket No. 133447-5010-WO

[0159] In some embodiments, the compound of formula (IA), formula (IIA), formula (IVA), and / or formula (VIA), or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, is a compound having a structure according to formula (VIIIA):O R2wherein in formula (VIIIA):R2is selected from H, Cl, Br, F, -CN, -OCH3, -N(CH3)2, -CH3, -CF3, cyclopropyl, and oxetanyl;Rdis selected from H, optionally substituted C1-C3 alkyl, -CD3, optionally substituted C3- C4 cycloalkyl, and optionally substituted 3- to 4-membered heterocycloalkyl;Rdis selected from H, optionally substituted C1-C3 alkyl, optionally substituted C3-C8 cycloalkyl, and optionally substituted 3- to 10-membered heterocycloalkyl;R5is independently at each occurrence selected from F, -CN, -CH3, -C(O)N(R5a)2, optionally substituted C3-C8 cycloalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 8-membered heterocycloalkyl;R5ais independently at each occurrence selected from H, optionally substituted C1-C3 alkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted3- to 6-membered heterocycloalkyl;n is 1, 2, or 3;R6and R6' are each independently selected from H, deuterium, halide, -CN, -OR6a, - NHR6a, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 haloalkyl, optionally substituted phenyl, optionally substituted C3-C6 cycloalkyl, optionally substituted5- to 6-membered heteroaryl, and optionally substituted 3- to 8-membered heterocycloalkyl; or R6and R6are taken together to form =C(R6b)2;DB1 / 166057797.1Docket No. 133447-5010-WOR6ais independently at each occurrence selected from H, optionally substituted C1-C3 alkyl, optionally substituted C1-C4 haloalkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocycloalkyl; andR6bis independently at each occurrence selected from H, deuterium, halide, C1-C3 alkyl, and C1-C3 haloalkyl.

[0160] In some embodiments of formula (VA), formula (VIA), formula (VIIA), and / or formula (VIIIA), Rdis selected from H, -CHF2, -CH3, -CH2CH3, -CH2OCH3, -CH2N(CH3)2, - CH2-azetidine, -CH(CH3)2, cyclopropyl, -CD3, and oxetane; wherein each azetidine, cyclopropyl, and oxetane moiety of Rdis optionally substituted with 1, 2, or 3 groups independently selected from -CH3, -CN, and oxo.

[0161] In some embodiments of formula (VA), formula (VIA), formula (VIIA), and / or formula (VIIIA), Rd' is selected from H, -CH3, -CH2CH3, -CH(CH3)2, -CH2OCH3, - CH2CH2OCH3, -CH2OH, -CH2CH2OH, -CH2N(CH3)2, -CH2CH2N(CH3)2, -CH2-azetidine, - CH(CH3)-azetidine, -CH2-oxetane, -CH(CH3)-oxetane, -CH2-diazaspiro[3.5]nonane, -CH2- diazaspiro[3.3]heptane, azaspiro[3.3]heptane, cyclopropyl, piperidine, pyrrolidine, pyrrolidinone, azetidine, oxetane, and tetrahydropyran; wherein each diazaspiro[3.5]nonane, diazaspiro[3.3]heptane, azaspiro[3.3]heptane, cyclopropyl, piperidine, pyrrolidine, pyrrolidinone, azetidine, oxetane, and tetrahydropyran moiety of Rdis optionally substituted with 1, 2, or 3 groups independently selected from -CH3, -CN, and oxo.

[0162] In some embodiments of formula (VA), formula (VIA), formula (VIIA), and / or formula (VIIIA), Rdis selected from H, -CHF2, -CH3, -CH2CH3, -CH2OCH3, -CH2N(CH3)2, - CH2-azetidine, -CH(CH3)2, cyclopropyl, -CD3, and oxetane; wherein each azetidine, cyclopropyl, and oxetane moiety of Rdis optionally substituted with 1, 2, or 3 groups independently selected from -CH3, -CN, and oxo; andRd' is selected from H, -CH3, -CH2CH3, -CH(CH3)2, -CH2OCH3, -CH2CH2OCH3, - CH2OH, -CH2CH2OH, -CH2N(CH3)2, -CH2CH2N(CH3)2, -CH2-azetidine, -CH(CH3)-azetidine, - CH2-oxetane, -CH(CH3)-oxetane, -CH2-diazaspiro[3.5]nonane, -CH2-diazaspiro[3.3]heptane, azaspiro[3.3]heptane, cyclopropyl, piperidine, pyrrolidine, pyrrolidinone, azetidine, oxetane, and tetrahydropyran; wherein each diazaspiro[3.5]nonane, diazaspiro[3.3]heptane, azaspiro[3.3]heptane, cyclopropyl, piperidine, pyrrolidine, pyrrolidinone, azetidine, oxetane, andDB1 / 166057797.1Docket No. 133447-5010-WOtetrahydropyran moiety of Rdis optionally substituted with 1, 2, or 3 groups independently selected from -CH3, -CN, and oxo.

[0163] In some embodiments of formula (VA), formula (VIA), formula (VIIA), and / or formula (VIIIA), Rd' is selected from -CH3, -CH2CH3, -CH(CH3)2, -CH2OCH3, -CH2CH2OCH3, - CH2OH, -CH2CH2OH, -CH2N(CH3)2, -CH2CH2N(CH3)2, cyclopropyl, piperidine, pyrrolidine,

[0164] In some embodiments of formula (IA), formula (IIA), formula (IVA), formula (VIA), and / or formula (VIIIA), R5is 5-membered heteroaryl optionally substituted with one or more of -Cl, -F, -OH, -CN, oxo, -CH3, -CF3, -CH2CH3, CH(CH3)2, cyclopropyl, -CH2-cyclopropyl, -CH2- azetidine, -CH2-oxetane, -CH2OCH3, -CH2OH, -CH2N(CH3)2, -C(O)NH2, -C(O)-azetidine, and - C(O)-morpholine.

[0165] In some embodiments of formula (IA), formula (IIA), formula (IVA), formula (VIA), and / or formula (VIIIA), R5is selected from -C(O)NH2, -C(O)NHCH3, -C(O)NHCH2CN, -DB1 / 166057797.1Docket No. 133447-5010-WOC(O)N(CH3)2, -C(0)-(5- to 6-membered heterocycloalkyl), -C(0)NH-(5- to 6-membered heteroaryl), and -C(0)NH-(4- to 6-membered heterocycloalkyl); wherein each heterocycloalkyl and heteroaryl is optionally substituted with one or more of -Cl, -F, -OH, -CN, oxo, -CH3, -CF3, - CH2CH3, -CH(CH3)2, cyclopropyl, and -CH2-cyclopropyl.

[0166] In some embodiments of formula (IA), formula (IIA), formula (IVA), formula (VIA), and / or formula (VIIIA), R5is independently at each occurrence selected from F, -CN, -CH3, - CF3, -C(O)NH2, -C(O)NHCH3, -C(O)NHCH2CN, -C(O)N(CH3)2, -NHC(O)CH3, -NHC(O)NH2,DB1 / 166057797.1Docket No. 133447-5010-WO

[0167] In some embodiments of formula (IA), formula (IIA), formula (IVA), formula (VIA), and / or formula (V111A), n is 1 or 2.

[0168] In some embodiments of formula (IA), formula (IIA), formula (IVA), formula (VIA), and / or formula (VIIIA), n is 1.

[0169] In some embodiments of formula (IA), formula (IIA), formula (IVA), formula (VIA), and / or formula (VIIIA), R6and R6'are each independently selected from H, deuterium, Cl, F, - CN, -OH, -OCH3, -NH-(optionally substituted C1-C3 alkyl), optionally substituted C1-C3 alkyl, optionally substituted C1-C3 haloalkyl, optionally substituted C3-C6 cycloalkyl, and optionally substituted 3- to 6-membered heterocycloalkyl; or R6and R6'are taken together to form =CH2.

[0170] In some embodiments of formula (IA), formula (IIA), formula (IVA), formula (VIA), and / or formula (VIIIA), R6and R6'are each independently selected from H, -OH, - NHCH2CH2OCH3, -CH3, -CH2CH3, -CH2OH, -CH2C(CH3)2OH, -CH2CH2OH, -CH2CH2OCH3, -CH2NH2, -CH2CN, -CH2CH2N(CH3)2,DB1 / 166057797.1Docket No. 133447-5010-WOcyclopropyl; or R6and R6are taken together to form =CH2.

[0171] In embodiments, any combination of the groups described above for the variables of formula (IA), formula (IIA), formula (IIIA), formula (IVA), formula (VA), formula (VIA), formula (VIIA), and formula (VIIIA), as defined and described herein, is contemplated herein, with the implicit proviso that such combination is in accordance with permitted valences of each specified group, variable, radical, or moiety. In embodiments, the combinations of specified groups, variables, radicals, or moieties of formula (IA), formula (IIA), formula (IIIA), formula (IVA), formula (VA), formula (VIA), formula (VIIA), and formula (VIIIA), are limited generally to those which result in the formation of stable or chemically feasible compounds (i.e., compounds which do not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, fragmentation, degradation, etc.).

[0172] In some embodiments, the compound according to formula (IA), formula (IIA), formula (IVA), formula (VIA), and / or formula (VIIIA), or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, is a compound having a structure according to any one of formula 1001-1351:Compound No. Structure Structure NameN-(l-cyclopropyl-lH- pyrazol-3 -y 1 )-3 -(7-((4-( 1,3 - dimethyl-5 -oxo- 1, 5 -dihy dro- 10014H- 1,2,4-triazol-4- yl)phenyl)ethynyl)-1-oxoisoindolin-2-yl)benzamideDB1 / 166057797.1Docket No. 133447-5010-WO3-(7-((4-(l,3-dimethyl-5-oxo- 1,5-dihydro-4H-l,2,4-triazol- 1002 4-yl)phenyl)ethynyl)- 1 - oxoisoindolin-2-yl)-N- methylbenzamideI N — ( / \ \ / ) - = - < / z / \x>w1 o 11\x°z3-(7-((4-(l,3-dimethyl-5-oxo- ° ° 'r / 1, 5-dihydro-4H- 1,2,4-triazol- 10034-yl)phenyl)ethynyl)-1-oxoisoindolin-2-yl)benzamideNH2\ZZ-I N— < / \=\ / ) - = - < / \=\ / >w 3-(7-((4-(l,3-dimethyl-5-oxo- 1, 5-dihydro-4H- 1,2,4-triazol- 100404-yl)phenyl)ethynyl)-l - oxoisoindolin-2-yl)-2- fluorobenzamide o^JNH2 / / CF3N^A / =\ / =\1 N — / ) - = - <\ / >W 5-(7-((4-(l,3-dimethyl-5-oxo- 1, 5-dihydro-4H- 1,2,4-triazol- 1005 ° 4-yl)phenyl)ethynyl)- 1 -oxo- 5-(trifluoromethyl)isoindolin- 2-yl)-2-fluorobenzamide °Y^NH2FDB1 / 166057797.1Docket No. 133447-5010-WO N^Z / \ / \I N— / ) - = — <\ / >W 5-(7-((4-(l,3-dimethyl-5-oxo- 1,5-dihydro-4H-l,2,4-triazol- 1006 ° 4-yl)phenyl)ethynyl)- 1 - '' z z— oxoi soindolin-2-yl)-2- fluorobenzamide ^^ °z°YYNH2FN^Z / =\ / =\I N — <■C r / ) - = - (\ N3-(4-((4-(l,3-dimethyl-5-oxo- 1 \ 1< O=^ o -Z—. 1, 5-dihydro-4H- 1,2,4-triazol- 4-yl)phenyl)ethynyl)-5-oxo- 1007 °5, 7 -dihy dro-6H-pyrrolo[3,4- aw b]pyridin-6-yl)-2- fluorobenzamide °yCNH2N^Z. / =\I N— <\ / ) - = - < fz / \x>3-(7-((4-(l,3-dimethyl-5-oxo- 1,5-dihydro-4H-l,2,4-triazol- ° ° 'r?4-yl)phenyl)ethynyl)- 1 - 1008oxoisoindolin-2-yl)-N-(l - methyl-lH-pyrazol-3- oy5j yl)benzamide N^ / NH~N' jN-(l -methyl-2-oxo- 1,2- dihy dro-3 -pyridyl)-m-(7- { 2- [p-(l-methyl-3-methyl-5-oxo- 10091, 5-dihydro-4H- 1,2,4-triazol- 4-yl)pheny 1] ethynyl } - 1 -oxo- 2-isoindolinyl)benzamideDB1 / 166057797.1Docket No. 133447-5010-WOI N— ( / z / \ = ( / zF~\x>wN-(5-chloro- 1 -methyl- 1H- ° ° pyrazol-3 -y 1 ) -3 -(7-((4-( 1, 3 - di m ethyl - 5-oxo-l,5-di hy dro- 10104H-l,2,4-triazol-4- oA j yl)phenyl)ethynyl)-1-oxoisoindolin-2-yl)benzamide N^ / NH— NZjClI N — A\ / ) - = - ( fz / \x>0 0IP N-(5-cyano-l-methyl-lH- pyrazol-3 -y 1 )-3 -(7-((4-( 1,3- dimethyl-5-oxo-l,5-dihydro- 10114H-l,2,4-triazol-4- yl)phenyl)ethynyl)- 1 - N^ / NH oxoisoindolin-2-yl)benzamide ^N' j / I N— AX / ) - = - ( fz / \x>3-(7-((4-(l,3-dimethyl-5-oxo- H 1, 5-dihydro-4H- 1,2,4-triazol- ° A? 4-yl)phenyl)ethynyl)- 1 - 1012 oxoisoindolin-2-yl)-N-(l- methyl-6-oxo- 1,6- oJU dihydropyrimidin-5- yl)benzamide \ / L / NHoDB1 / 166057797.1Docket No. 133447-5010-WO / / CF3I N— ( fZ / \ b — = — < fz / \x>\ / \ / 3-(7-((4-(l,3-dimethyl-5-oxo- 1, 5-dihydro-4H- 1,2,4-triazol- 1013 4-yl)phenyl)ethynyl)- 1 -oxo- 5 -(trifluoromethyl)i soindolin- 2-yl)-N-methylbenzamide °Y*U^NH / / CF3N=A / =\ / \I N— (\ / ) - = - (\ / >W 3-(7-((4-(l,3-dimethyl-5-oxo- 1, 5-dihydro-4H- 1,2,4-triazol- 101404-yl)phenyl)ethynyl)- 1 -oxo-F\ / A 5-(trifluoromethyl)isoindolin- 2-yl)-2 -fluorobenzamide oJNH2N^\I N— ( fz / \ = < / \=\ / >^ ^=7 \ J 3-(7-((4-(l,3-dimethyl-5-oxo- 1, 5-dihydro-4H- 1,2,4-triazol- 1015 ° 4-yl)phenyl)ethynyl)- 1 - oxoisoindolin-2-yl)-2,6- difluoro-N-methy lb enzami de °Y Y^NH F7Z=\I N — / ) - = - / >w 3-(7-((4-(l,3-dimethyl-5-oxo- 1, 5-dihydro-4H- 1,2,4-triazol- 1016 ° 4-yl)phenyl)ethynyl)-l- oxoi soindolin-2-yl)-2-fluoro- N-methylbenzamide oJU^NHDB1 / 166057797.1Docket No. 133447-5010-WOh|A\ / \3-(7-((4-(l,3-dimethyl-5-oxo- 1, 5-dihydro-4H- 1,2,4-triazol- 1017 ° 4-yl)phenyl)ethynyl)-l- oxoi soindolin-2-yl)-2-fluoro- N-hydroxybenzamide / NHHO1 N— < / \=\ / ) - = - / =\ / >W 5-(7-((4-(l,3-dimethyl-5-oxo- 1, 5-dihydro-4H- 1,2,4-triazol- 101804-yl)phenyl)ethynyl)-l- oxoi soindolin-2-yl)-2-fluoro- N-methylbenzamide^NH F / FNA / =\ A xI N— <\ / ) - = - <\ / >w 3-(7-((4-(l,3-dimethyl-5-oxo- 1, 5-dihydro-4H- 1,2,4-triazol- 1019 ° 4-yl)phenyl)ethynyl)-5- fluoro- 1 -oxoi soindolin-2- yl)benzamide °yC)NH2 / Fi NHZ— = — <Z X>^ ^=7 V / N-(cyanomethyl)-3-(7-((4- (l,3-dimethyl-5-oxo-l,5- dihydro-4H-1,2,4-triazol-4- 10200°A>yl)phenyl)ethynyl)-5-fluoro- 1 -oxoi soindolin-2- yl)benzamide °vXjN<x 1^\ / NHDB1 / 166057797.1Docket No. 133447-5010-WO / FN^A f / \ f / \1 N — <z= <z x>-A H 3-(7-((4-(l,3-dimethyl-5-oxo- 1, 5-dihydro-4H- 1,2,4-triazol- 4-yl)phenyl)ethynyl)-5- 1021fluoro- 1 -oxoisoindolin-2-yl)- N-(lH-pyrazol-3- yl)benzamide N^ / NHHNZj / FN^A / =\ / r\<I N— (\ / ) - = - \ / V / N-( 1 -cyclopropyl- 1 H- pyrazol-3 -y 1 ) -3 -(7-((4-( 1, 3 - °oaA di m ethyl - 5-oxo-l,5-di hy dro- 1022 4H-l,2,4-triazol-4- yl )phenyl)ethynyl)-5 -fluoro- 1 -oxoi soindolin-2- oJJyl)benzamide.ZN^ / NHLA— NZJr"0AA / / i NAX) — = — (Z X> 3-(7-((4-(l,3-dimethyl-5-oxo- V / l,5-dihydro-4H-l,2,4-triazol- 4-yl)phenyl)ethynyl)-5- 10230AV (oxetan-3-yl)-l- oxoisoindolin-2-yl)-N- methylbenzamide yl)benzamide.^NHDB1 / 166057797.1Docket No. 133447-5010-WO / FI N— ( f' / \ = — < f / \Wz x>3-(7-((4-(l,3-dimethyl-5-oxo- 1, 5-dihydro-4H- 1,2,4-triazol-04-yl)phenyl)ethynyl)-5- 1024fluoro- 1 -oxoisoindolin-2-yl)- N-( 1 -methyl- IH-py razol-3 - oAj yl)benzamide N^ / NH~NZj / =\ / / \I N— (\ / > - = - <z x> / N-^ \ _ ( / \ _ / N-( 1 -(cyclopropylmethyl)-0o-Q lH-pyrazol-3-yl)-3-(7-((4- (l,3-dimethyl-5-oxo-l,5- 1025dihydro-4H-1,2,4-triazol-4- yl)phenyl)ethynyl)-1-oxoisoindolin-2-yl)benzamide \ zN^r / NH^NZj\ FN=X / =\w 3 -(5 -fluoro-7 -((4 - (3 -methoxy- 1 -m ethyl - 5 -oxo- 1, 5 -di hy dro- 10260 04H- 1,2,4-triazol-4- yl)phenyl)ethynyl)-1-oxoisoindolin-2-yl)benzamide °Y6NH2DB1 / 166057797.1Docket No. 133447-5010-WO\)N^X / =\ / =\I N— <\ / ) - = - (\ / >w 3-(7-((4-(3-methoxy-l- methyl-5-oxo-l,5-dihydro- 4H- 1,2,4-triazol-4- °1027 yl)phenyl)ethynyl)- 1 - oxoisoindolin-2-yl)-N-(l - methyl-lH-pyrazol-3- yl)benzamide N^ / NH— N' yN 1X. N— < / \=\ / > - = - < / \=\ / >w N-( 1 -(cyclopropylmethyl)- lH-pyrazol-3-yl)-3-(7-((4-(3- °0r / methoxy- 1 -methyl-5-oxo-l,5- 1028dihydro-4H-1,2,4-triazol-4- yl)phenyl)ethynyl)- 1 - OyV5oxoisoindolin-2-yl)benzamide \ N^ / NHx— NZJN IX N— / =\ / > - = - / =\ / > 3-(7-((4-(3-methoxy-l- wmethyl-5-oxo- 1, 5-dihy dro- 4H- 1,2,4-triazol-4-0yl)phenyl)ethynyl)- 1 - 1029oxoisoindolin-2-yl)-N-(l - methyl-6-oxo-l,6- o °> JU dihydropyrimidin-5- yl)benzamide \ JL, NHoDB1 / 166057797.1Docket No. 133447-5010-WO \)N^X / =\ / =\1 N— <\ / ) - = - <\ / > / N-X V7 W N-(l-cyclopropyl-lH- pyrazol-3-yl)-3-(7-((4-(3- ° ° 'r / methoxy- 1 -methyl-5-oxo- 1,5- 1030dihydro-4H-1,2,4-triazol-4- yl)phenyl)ethynyl)-1-oxoisoindolin-2-yl)benzamide N^ / NH\) H ° FN=X / =\I N— / ) h -11= ° - / >w 3-(5-fluoro-7-((4-(3-methoxy- 1 -m ethyl - 5 -oxo- 1, 5 -di hy dro-4H-l,2,4-triazol-4- °0'r / 1031 yl)phenyl)ethynyl)- 1 - oxoisoindolin-2-yl)-N-(l- methyl-lH-pyrazol-3- \z Z—°y6 yl)benzamide N^ / NH^NZjN-(l-cyclopropyl-lH- pyrazol-3-yl)-3-(5-fluoro-7- ((4-(3-methoxy-l-methyl-5- 1032 oxo- 1,5-dihydro-4H- 1,2,4- triazol-4-yl)phenyl)ethynyl)- 1 -oxoisoindolin-2- yl)benzamideDB1 / 166057797.1Docket No. 133447-5010-WO\> FN=X / ==\ / =<\I N— (\ / ) - = - / >w N-(l-(cyclopropylmethyl)- 1 H-pyrazol-3 -y 1 ) - 3 -(5 -fluoro- 7-((4-(3-methoxy-l-methyl-5- °0'r?1033 oxo- 1, 5 -dihy dro-4H- 1,2,4- triazol-4-yl)phenyl)ethynyl)- 1 -oxoi soindolin-2- °yU yl)benzamide \ / N^XNH^NZj\> FN=X / =\ / =<\1 N— (\ / ) - = - / >wN-(5-cyano-l-methyl-lH-0°^l< pyrazol-3-yl)-3-(5-fluoro-7- ((4-(3 -methoxy- 1 -methyl -5- 1034 oxo- 1,5-dihydro-4H- 1,2,4- triazol-4-yl)phenyl)ethynyl)- <yd) 1 -oxoisoindolin-2-zN^ / NH yl)benzamide ~NZj / N / F / NJ W 3 -(7 -((4-( 1, 3 -dimethyl -5 -oxo- 1, 5-dihydro-4H- 1,2,4-triazol-04-yl)phenyl)ethynyl)-5- 1035 fluoro- 1 -oxoisoindolin-2-yl)- N-( 1 -methyl-6-oxo- 1,6- °UJ dihydropyrimidin-5- yl)benzamide \ JL / NHkJDB1 / 166057797.1Docket No. 133447-5010-WO / FN^A f / \i NAX) — = — <Z X>\ _ / \ _ / 3-(7-((4-(l,3-dimethyl-5-oxo- 1, 5-dihydro-4H- 1,2,4-triazol-0AV 4-yl)phenyl)ethynyl)-5- 1036 fluoro- 1 -oxoi soindolin-2-yl)- N-(l -methyl-2-oxo- 1,2- °jO dihy dropyri din-3 - yl)benzamide\ JL / NHV / FNA / / \ f / \2^ AV W 3-(7-((4-(l,3-dimethyl-5-oxo- 1, 5-dihydro-4H- 1,2,4-triazol- 10370AN7 4-yl)phenyl)ethynyl)-5- fluoro- 1 -oxoisoindolin-2-yl)- N-methylbenzamide^NHM NA-" A / / W \\ / / n^\1 N — <z x> - = - <z x>W 3-(4-((4-(l,3-dimethyl-5-oxo- 1, 5-dihydro-4H- 1,2,4-triazol- 4-y l)pheny l)ethynyl)-3 -oxo- 10380°AN>l,3-dihydro-2H-pyrrolo[3,4- c]pyridin-2-yl)-N- methylbenzamide ^, NH.N. A n — \ z^I \ N — < / z / \x\N) - = - ( / z / wx>^ AA W 3-(7-((4-(l,3-dimethyl-5-oxo- 1, 5-dihydro-4H- 1,2,4-triazol- 4-yl)phenyl)ethynyl)- 1 -oxo- 10390l,3-dihydro-2H-pyrrolo[3,4- c]pyridin-2-yl)-N- methylbenzamide °UJ^NHDB1 / 166057797.1Docket No. 133447-5010-WO I N — <z x) - = - <zNV / 3 -(4-((4-( 1, 3 -dimethyl-5 -oxo- 1, 5-dihydro-4H- 1,2,4-triazol- 4-yl)phenyl)ethynyl)-5-oxo- 10400 oS^iT5, 7 -dihy dro-6H-pyrrolo[3,4- b]pyridin-6-yl)-N- methylbenzamide ^NHI N— < / \=\ / > - = - < fz / \x>w l-(3-(7-((4-(l,3-dimethyl-5- oxo- 1,5-dihydro-4H- 1,2,4- 1041 °0'r? triazol-4-yl)phenyl)ethynyl)- l-oxoisoindolin-2-yl)phenyl)- 3 -methylureaH HN^\ / =\ / =\I N— / ) - = - / >w 3 -(7-((4-(3 -methoxy- 1- methyl-5-oxo-l,5-dihydro- 1042 °04H- 1,2,4-triazol-4- yl)phenyl)ethynyl)-1-oxoisoindolin-2-yl)benzamide OyZ)NH2 / =\ f / 1I N— <\ / ) - = - <z x>3 -(4-((4-( 1,3 -dimethyl-5-oxo- 1, 5-dihydro-4H- 1,2,4-triazol-0O^r / oH1043 4-yl)phenyl)ethynyl)-l- hydroxy-3-oxoisoindolin-2- yl)-N-methylbenzamide °y6^NHDB1 / 166057797.1Docket No. 133447-5010-WO / F\ / / \ f / \I N— (z x> — = — <z x>W 3-(7-((4-(l,3-dimethyl-5-oxo- 1, 5-dihydro-4H- 1,2,4-triazol- 1044 ° 4-yl)-3- z fluorophenyl)ethynyl)- 1 - oxoisoindolin-2-yl)benzamide °yCjNH2S (11 o3-(7-((2-cyano-4-(l,3- O z—dimethyl-5-oxo-l,5-dihydro- 4H- 1,2,4-triazol-4- 1045yl)phenyl)ethynyl)-5-fluoro- l-oxoisoindolin-2- yl)benzamide, N / / FNA f / \ f / 43-(7-((2-cyano-4-(l,3- ^ ^=7 W di m ethyl - 5-oxo-l,5-di hy dro- 4H-l,2,4-triazol-4- 1046° yl)phenyl)ethynyl)-5-fluoro- 1 -oxoi soindolin-2-yl )-N- methylbenzamide yl)benzamide.^NH / F / =\ f / 1I N— (\ / ) — = — (z x>3-(7-((5-(l,3-dimethyl-5-oxo- 1,5-dihydro-4H-l,2,4-triazol- 104704-yl)pyridin-2-yl)ethynyl)-5- fluoro- 1 -oxoisoindolin-2-yl)- N-methylbenzamide °y6^NHDB1 / 166057797.1Docket No. 133447-5010-WO 1 N— e f / x) — = — < / \ \ / >W N-(3-(7-((4-(l,3-dimethyl-5- oxo- 1, 5 -dihy dro-4H- 1,2,4- 1048Otriazol-4-yl)phenyl)ethynyl)- 1 -oxoi soindolin-2- o r ii yl)phenyl)acetamide A HXJ3 -(4-((4-( 1,3 -dimethyl-5-oxo- 9- Q9= 1, 5-dihydro-4H- 1,2,4-triazol- 1049 1 11 o cf 11 \ \ ° ° 4-yl)phenyl)ethynyl)- 1,1- dimethyl-3-oxoisoindolin-2- yl)-N-methylbenzamide 9 9yy / Ooz^ z z Z Z——3 -(4-((4-(3 -methoxy- 1 - methyl-5-oxo-l,5-dihydro- 4H-l,2,4-triazol-4- 1050yl)phenyl)ethynyl)- 1,1- dimethyl-3-oxoisoindolin-2- yl)-N-methylbenzamide N=X / \ / / \I N— <\ / > - = - (z x>y / 3 -(4-((4-( 1, 3 -dimethyl -5 -oxo- 1, 5-dihydro-4H- 1,2,4-triazol- 10510° '9'' 4-yl)phenyl)ethynyl)- 1 - methyl-3-oxoisoindolin-2-yl)- N-methylbenzamide oJU^NHDB1 / 166057797.1Docket No. 133447-5010-WO3 -(4-((4-( 1, 3 -dimethyl-5 -oxo- 1, 5-dihydro-4H- 1,2,4-triazol- 4-yl)phenyl)ethynyl)- 1 -(2- 1052hydroxyethyl)-3- oxoisoindolin-2-yl)-N- methylbenzamide O3-(4-((4-(l,3-dimethyl-5-oxo- 1, 5-dihydro-4H- 1,2,4-triazol- 11 °1053 1 o \ 11 ° 4-yl)phenyl)ethynyl)- 1 - methylene-3-oxoisoindolin-2- yl)-N-methylbenzamide\z Z—\HI N— ( / \=\ / ) - = - < fz / \x> 3 -(7 -((4-(3 -methoxy- 1 - wmethyl-5-oxo-l,5-dihydro- 4H- 1,2,4-triazol-4- 1054 °0rP yl)phenyl)ethynyl)- 1 - oxoisoindolin-2-yl)-N- methylbenzamide^NHO-NX / =\I N— <\ / ) - = - ((x>3-(7-((4-(l,2-dimethyl-3,5- dioxo-l,2,4-triazolidin-4- 1055 ° yl)phenyl)ethynyl)- 1 - oxoisoindolin-2-yl)-N- methylbenzamide oy6^NHDB1 / 166057797.1Docket No. 133447-5010-WON, N-dimethyl-4-((2-(3- 1 (methylcarbamoyl)phenyl)-3- 1056oxoisoindolin-4- \z- yl)ethynyl)benzamide J\ \ / Q Z>.d6 60 III I O O \ \II II O O \ \^fl O O Z z—— 3-(7-((4- t^ O O Z Z—— acetamidophenyl)ethynyl)-l- 1057oxoisoindolin-2-yl)-N- aw methylbenzamide w aN-methyl-3-(7-((4-(3-methyl- 2-oxo-2,3 -dihydro- 1 H- 1058 imidazol-1- yl)phenyl)ethynyl)-1-oxoisoindolin-2-yl)benzamide3 -(7 -((4-(3 -i sopropyl - 1 - methyl-5-oxo-l,5-dihydro- 4H- 1,2,4-triazol-4- 1059yl)phenyl)ethynyl)- 1 - oxoisoindolin-2-yl)-N- methylbenzamideDB1 / 166057797.1Docket No. 133447-5010-WO3 -(7-((4-( 1 -i sopropy 1 -5 -oxo- 1, 5-dihydro-4H- 1,2,4-triazol- 1060 4-yl)phenyl)ethynyl)-l- oxoisoindolin-2-yl)-N- methylbenzamide 7dN-methyl-3-(7-((4-(l-methyl- II O \^q o- 5-oxo-1,5-dihydro-4H-1,2,4- 1061 1 II o o 11\x11x11 ^ °°zo z — ° triazol-4-yl)phenyl)ethynyl)- 1 -oxoi soindolin-2- yl)benzamide awy / o^ \ / z z\—\ ZZ- J3N-methyl-3-(l-oxo-7-((4-(5- I oxo-4, 5 -dihydro- 1H-1, 2,4- 1062 triazol-1- yl)phenyl)ethynyl)isoindolin-2-yl)benzamide3 -(7-((4-(3 -(difluoromethyl)- 1 -m ethyl - 5 -oxo- 1, 5 -di hy dro- 4H- 1,2,4-triazol-4- 1063yl)phenyl)ethynyl)- 1 - oxoisoindolin-2-yl)-N- methylbenzamideDB1 / 166057797.1Docket No. 133447-5010-WON-methyl-3-(7-((4-(4-methyl- 5-oxo-4,5-dihydro-lH-l,2,4- 1064 triazol-l-yl)phenyl)ethynyl)- I K) 1 -oxoi soindolin-2- z yl)benzamide X^^ °1 [0*II o \ N-methyl-3-(l-oxo-7-((4-(3- 1065 iiJ ' O z oxomorpholino)phenyl)ethyn I° M..—° yl)isoindolin-2-yl)benzamide6-((2-(3- (methylcarbamoyl)phenyl)-3- 1066 oxoisoindolin-4- yl)ethynyl)isochromane-l- carboxamideN-methyl-3 -( 1 -oxo-7-((4-(2- 1067 oxocyclohexyl)phenyl)ethyny l)isoindolin-2-yl)benzamideDB1 / 166057797.1Docket No. 133447-5010-WON-methyl-3 -( 1 -oxo-7-((4-(2- oxopyrrolidin-1- 1068yl)phenyl)ethynyl)isoindolin-2-yl)benzamideN-methyl-3 -( 1 -oxo-7-((4-(2- oxopiperidin-1- 1069 11 II Ox11 ' °° yl)phenyl)ethynyl)isoindolin-2-yl)benzamide 10? Co z- N-methyl-3-(7-((4-(3-methyl- 5-oxo-1,2,4-oxadiazol-4(5H)- 1070yl)phenyl)ethynyl)-1-oxoisoindolin-2-yl)benzamide / \ / \HN^ V7 W N-methyl-3-(7-((4-(3-methyl- 5-oxo-1,5-dihydro-4H-1,2,4- 1071 triazol-4-yl)phenyl)ethynyl)- 1 -oxoisoindolin-2- yl)benzamide^NHDB1 / 166057797.1Docket No. 133447-5010-WO / FI N— < fz / \x) - = - < fz / \x>3-(7-((4-(1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)-2- 1072methoxyphenyl)ethynyl)-5- z fluoro- 1 -oxoi soindolin-2-yl)- N-methylbenzamide ^NH / FN=A / \ 1i N— ex> — = II O \ — <z x> 3-(7-((4-(1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)-2- 1073fluorophenyl)ethynyl)-5- %At- fluoro- 1 -oxoisoindolin-2-yl)- N-methylbenzamide °ytj^NH3 -(5 -fluoro-7-((4-(3 -methoxy- 1 -methyl - 5 -oxo- 1, 5 -dihy dro- 4H- 1,2,4-triazol-4- 1074yl)phenyl)ethynyl)- 1 - oxoisoindolin-2-yl)-N- methylbenzamide / \ Fh|A\ / \ 1I N— (z x> - = - <z x> 3-(7-((4-(1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)-2- 10750methoxyphenyl)ethynyl)-5- fluoro- 1 -oxoi soindolin-2- yl)benzamide °y6NH2DB1 / 166057797.1Docket No. 133447-5010-WO / F FNA f / \ f / \I N — <z x) - = - <z x>3-(7-((4-(1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)-2- 10760 0fluorophenyl)ethynyl)-5- fluoro- 1 -oxoi soindolin-2- yl)benzamide °yC)NH2 / FN^A / / f / \I N — <z x) - = - <z x>^ ^=7 W 3-(7-((4-(1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)-2- 1077 ° °A;fluorophenyl)ethynyl)- 1 - oxoisoindolin-2-yl)-N- methylbenzamide ojj^NH / F\N^A / / \ / / \I N — <z x> - = - <z x>3-(7-((4-(l,3-dimethyl-5-oxo- W1, 5-dihydro-4H- 1,2,4-triazol- 4-yl)-3- 1078 ° °A>fluorophenyl)ethynyl)- 1 - oxoisoindolin-2-yl)-N- methylbenzamide oji^NHf / f / \i NAX) — = — <Z X>3-(7-((4-(1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)-2- 1079methylphenyl)ethynyl)-l- oxoisoindolin-2-yl)-N- methylbenzamide ^NHDB1 / 166057797.1Docket No. 133447-5010-WO / / °FI N— < fz / \x> - = - < fz / \x> 3-(7-((2-acetyl-4-(l,3- \ _ / \ _ / di m ethyl -5 -oxo- 1, 5 -di hy dro- 4H-l,2,4-triazol-4- 1080^zz— yl)phenyl)ethynyl)-5-fluoro- 1 -oxoi soindolin-2- yl)benzamideNH2dx3-(7-((4-(1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)-2- 1081 iA> fluorophenyl)ethy nyl)- 1 - oxoisoindolin-2-yl)benzamideNX f / f / \I N— (z x> — = — <z x>w 3-(7-((4-(1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)-2- 1082 methylpheny l)ethynyl)- 1 - oxoisoindolin-2-yl)benzamide oy6NH2NX / / \ f / \I N— (z x) (z x>H 7-((4-(1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl)ethynyl)-2-(3-(4- methyl-1H-1,2,3-triazol-1- yl)phenyl)isoindolin- 1 -one XJ\ 1VNDB1 / 166057797.1Docket No. 133447-5010-WOI N — / =\ / ) - = — <z x>V / 2-(3-(1H-imidazol-2-yl)phenyl)-7-((4-(1,3-dimethyl-5-oxo-1,5-dihydro- 10840° 'X4H- 1,2,4-triazol-4- yl)phenyl)ethynyl)isoindolin- NYJ6 1-oneX-NH / X X\I N— <zX - = - <\ / >7-((4-(1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol- 108504-yl)phenyl)ethynyl)-2-(3-(2- methyl-1H-imidazol-5- yl)phenyl)isoindolin-l-one JN^X / =\ XXI N— (\ / > — = - / > 2-(3 -( 1 H-imidazol-2- w yl)phenyl)-7-((4-(3-methoxy- 1 -methyl - 5 -oxo- 1, 5 -dihy dro- 1086 ° X 4H- 1,2,4-triazol-4- yl)phenyl)ethynyl)isoindolin- 1-one ^6^XNH\> F / =\ / =<\I NX\ / ) - = - / > 2-(3 -( 1 H-imidazol-2- w yl)phenyl)-5-fluoro-7-((4-(3- methoxy- 1 -methyl-5-oxo-l,5- 10870O^'-N^ dihydro-4H-1,2,4-triazol-4- yl)phenyl)ethynyl)isoindolin- 1-oneX-NHDB1 / 166057797.1Docket No. 133447-5010-WON II. N— / \ / > — = — < fz / \x>w 7-((4-(1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol- 108804-yl)phenyl)ethynyl)-2-(3- (pyrazin-2- yl)phenyl)isoindolin-l-one I AN11 o N-methyl-m-(7-{2-[p-(2-hydroxycyclohexyl)phenyl]et 1089hynyl}-l -oxo-2- isoindolinyl)benzamide \ o / =\\ II / \ / / \HN-S— / > - = - <z x>II / / \ _ / ° - / - \ N-methyl-m-(7-{2-[p- (methylaminosulfonyl)phenyl 1090] ethyny 1 } - 1 -oxo-2- i soindolinyl)benzami de oyd^, NH / =\ / / \N-methyl-m-{7-[2-(p-{1-[(3- azetidinyl)methyl]-3-methyl- 5-oxo-1,5-dihydro-4H-1,2,4- 1091 A0triazol-4-yl }phenyl)ethynyl]- N1 -oxo-2-H1 1 isoindolinyl}benzamide^NHDB1 / 166057797.1Docket No. 133447-5010-WO / \ / \I N— / ) - = - / )— NH 2-((7-((4-(1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl)ethynyl)- 9z z— 2-(3- 10920o-vn->- (methylcarbamoyl)phenyl)- 1 - oxoisoindolin-4- yl)amino)oxazole-5- carboxamide ^NH6 II? \ / K O -Z—.\ |\ I \ _1 o 11x° N-[p-(2-{3-oxo-2-[m-(N- 11 o methylcarbamoyl)phenyl]-4- 1093 COOH isoindolinyl }ethynyl)phenyl]- 5 -pyrazol ecarb oxami de to a ° / ■Z.I I K>y IZZ / \z=73 -(7-((4-(3 -hy droxy-2- oxopiperidin-1- 1094 yl)phenyl)ethynyl)- 1 - oxoisoindolin-2-yl)-N- methylbenzamide5-[(7-{2-[p-(1-methyl-3-methyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4- yl)phenyl]ethynyl } - 1 -oxo-2- 1095[m-(N- methylcarbamoyl)phenyl]-4- isoindolinyl)methyl]-3- pyrrolecarboxamideDB1 / 166057797.1Docket No. 133447-5010-WOm-(5-fluoro-7-{2-[3- methoxy-4-(l -methyl-3- methyl-5-oxo- 1, 5-dihy dro- 1096' A''z zz—- 4H-1,2,4-triazol-4-yl)phenyl]ethynyl}-1-oxo-2-isoindolinyl)benzamide / F1 N— ( / \=\ / ) - = 1111 o o - < fz / \x>^ o o ~Z—. W m-(5 -fluoro-7 -{2-[5-(l- methyl-3-methyl-5-oxo-l,5- 10970dihydro-4H-1,2,4-triazol-4- l6b> yl)-2-py ridyl]ethyny 1 } - 1 -oxo- 2-isoindolinyl)benzamide °Y6NH2N / \FN=A / =\1 N— <\ / ) - = - ( fz / \x> m-(7-{2-[3-cyano-4-(l- methyl-3-methyl-5-oxo-l,5- dihydro-4H-1,2,4-triazol-4- 10980yl)pheny 1] ethy nyl } -5 -fluoro- l-oxo-2- i soindolinyl)benzami de <y^NH2m-(7-{2-[4-(1-methyl-3-methyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)-3-tolyl]ethynyl}-1-oxo-2- isoindolinyl)benzamideDB1 / 166057797.1Docket No. 133447-5010-WON -methy l-m-(7 - { 2- [4 -( 1 - methyl-3-methyl-5-oxo-l,5- 1100 dihydro-4H-1,2,4-triazol-4- y 1 ) -3 -toly l]ethynyl } - 1 -oxo-2- isoindolinyl)benzamide / F\ / =\ / / \I N— / > - = - QA? (z x>w 3-(7-((4-(1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl)ethynyl)-6-fluoro-1-oxoisoindolin-2-yl)benzamide 1101NH2z z—I N— / =\ / ) - = - ( fz / \ 7 — FLT3-(7-((4-(1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl)ethynyl)-4-fluoro-1-oxoisoindolin-2- yl)benzamide NH2N-(5-cyano- 1 -methyl-3 - pyrazolyl)-m-(7-{2-[p-(3- methoxy- 1 -methyl-5-oxo-l,5- 1103dihydro-4H-1,2,4-triazol-4- yl)phenyl]ethynyl } - 1 -oxo-2- isoindolinyl)benzamideDB1 / 166057797.1Docket No. 133447-5010-WO I N— ( fz / \x) — = — < fz / \x>3-(7-((4-(1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl)ethynyl)-1- 1104 — ° / \ \01— oxoi soindolin-2-yl)-2- \ \ ZZ 1 z z——J V methylbenzamide ^S"iO / O'zoCUNH266II O \ON-methyl-3-(7-((4-(l-methyl- 3-(oxetan-3-yloxy)-5-oxo- 1105 1, 5-dihydro-4H- 1,2,4-triazol- 4-yl)phenyl)ethynyl)-1-oxoisoindolin-2-yl)benzamideN-methyl-3-(7-((4-(l-methyl- 5-oxo-3-((tetrahydro-2H- py ran-4-y l)oxy )- 1, 5 -dihy dro- 11064H- 1,2,4-triazol-4- yl)phenyl)ethynyl)-1-oxoisoindolin-2-yl)benzamideDB1 / 166057797.1Docket No. 133447-5010-WO / \ f / \3 -(7-((4-(3 -ethoxy- 1 -methyl- 5-oxo- 1, 5-dihydro-4H- 1,2,4- 1107 z triazol-4-yl)phenyl)ethynyl)- °0l-oxoisoindolin-2-yl)-N- methylbenzamide d ^. NH11 o1XN — <f 7 -^ = O z - < / x=\ z>M 3-(7-((4-(3-methoxy-4- methyl-5-oxo-4,5-dihydro- ° lH-l,2,4-triazol-l- 1108yl)phenyl)ethynyl)- 1 - oxoisoindolin-2-yl)-N- oyd) methylbenzamide ^NH\)N I^\ / Z\ \^ N—A (= / X) — = — W (Z X> 3-(4-((4-(3 -methoxy- 1 - methyl-5-oxo-l,5-dihydro- 4H-l,2,4-triazol-4- 11090y l)phenyl)ethyny 1)- 1,1- dimethyl-3-oxoisoindolin-2- yl)benzamide cyCbNH23 -(4-((4-( 1, 3 -dimethyl -5 -oxo- 1, 5-dihydro-4H- 1,2,4-triazol- 1110 4-yl)phenyl)ethynyl)- 1,1- dimethyl-3-oxoisoindolin-2- yl)benzamideDB1 / 166057797.1Docket No. 133447-5010-WO\)1 N— < fz / \ 7 — = — ( / z / \ 7 2-(3-(lH-imidazol-2- yl)phenyl)-7-((4-(3-methoxy- 1 -m ethyl - 5 -oxo- 1, 5 -di hy dro- mi ° °7A 4H-l,2,4-triazol-4- y l)phenyl)ethynyl)-3,3 - dimethylisoindolin- 1 -one < KJJV-N III N — < fz / \ 7 — = — < fz / \ 72-(3-(lH-imidazol-2- W yl)phenyl)-7-((4-(l,3- dimethyl-5-oxo-l,5-dihydro- 11120A v4H-l,2,4-triazol-4- y l)phenyl)ethyny l)-3,3 - H JM dimethylisoindolin- 1 -one < VN iiXO FN^X / N— (=\ / Ci \ / ) — = — (z7 3-(6-fluoro-4-((4-(3-methoxy- 1 -m ethyl - 5-oxo-l,5-dihy dro- W4H-l,2,4-triazol-4- 11130AA yl)phenyl)ethynyl)- 1,1- dimethyl-3-oxoisoindolin-2- yl)-N-methylbenzamide ^. NH\) F / =\ / / CI N-(\ / > — — <z7 3-(6-fluoro-4-((4-(3-methoxy- 1 -m ethyl - 5 -oxo- 1, 5 -di hy dro- A 4H- 1,2,4-triazol-4- 11140A A y l)phenyl)ethynyl)- 1,1- dimethyl-3-oxoisoindolin-2- yl)benzamide oy6NH2DB1 / 166057797.1Docket No. 133447-5010-WO / F / =\ / / \I N — / ) — = — <z73 -(4-((4-( 1, 3 -dimethyl-5 -oxo- 1, 5-dihydro-4H- 1,2,4-triazol- 1115 ° < < 4-yl)phenyl)ethynyl)-6- \z- fluoro- 1, 1 -dimethy 1-3 - oxoisoindolin-2-yl)benzamide NH2 / FI N— < / \=\ / ) - = - ( / z / \ 711 o 3 -(4-((4-( 1, 3 -dimethyl -5 -oxo- ^ o -Z—. 1, 5-dihydro-4H- 1,2,4-triazol- 4-yl)phenyl)ethynyl)-6- 11160< AAfluoro- 1, 1 -dimethy 1-3 - oxoisoindolin-2-yl)-N- methylbenzamide ^NH / / °FN" A f / \ f / \3-(7-((2-acetyl-4-(l,3- W dimethyl-5 -oxo- 1, 5 -dihy dro- 4H- 1,2,4-triazol-4- 11170yl)phenyl)ethynyl)-5-fluoro- l-oxoisoindolin-2-yl)-N- methylbenzamide ^NH3 -(7 -((4-( 1, 3 -dimethyl -5 -oxo- 1, 5-dihydro-4H- 1,2,4-triazol- 4-yl)-3- 1118((dimethylamino)methyl)phen yl)ethynyl)- 1 -oxoisoindolin- 2-yl)benzamideDB1 / 166057797.1Docket No. 133447-5010-WO HN / O I N — f / \ / =\ / > N-methyl-3-(7-((4-(l-methyl- W 5-oxo-3-(pyrrolidin-3-yloxy)- 1119 1, 5-dihydro-4H- 1,2,4-triazol-04-yl)phenyl)ethynyl)- 1 - oxoi soindolin-2-yl)benzamide ^. NHW CCHN — |II o 11 M \ °ON^\ f / \ / =\ 3-(7-((4-(3-(azetidin-3- i N — ex> — = — <\ / >yloxy)-l-methyl-5-oxo-l,5-? C H dihydro-4H-1,2,4-triazol-4- 1120yl)phenyl)ethynyl)- 1 - \ r\ °oxoisoindolin-2-yl)-N- \ZZ~' methylbenzamide ^NH3 -(7-((4-(3 -(azeti din-3 - ylmethoxy)- 1 -methyl-5-oxo- 1, 5-dihydro-4H- 1,2,4-triazol- 11214-yl)phenyl)ethynyl)- 1 - oxoisoindolin-2-yl)-N- methylbenzamideDB1 / 166057797.1Docket No. 133447-5010-WO HN'"\0I N — ( / z / \ / =\ / > N-methyl-3-(7-((4-(l-methyl- 5-oxo-3-(piperidin-4-yloxy)- 1122 \ i — W1 ~Z~Z.. 1, 5-dihydro-4H- 1,2,4-triazol- 1 v04-yl)phenyl)ethynyl)-1-oxoisoindolin-2-yl)benzamide 6^NHII o \II o II \ty ° O Z—N-methyl-3-(7-((4-(l-methyl- 3-((l-methylazetidin-3- yl)oxy)-5-oxo-l,5-dihydro- 11234H- 1,2,4-triazol-4- Hr yl)phenyl)ethynyl)-1-oxoisoindolin-2-yl)benzamide3-(7-((4-(3-(l- cyanocyclopropoxy )- 1 - methyl-5-oxo-l,5-dihydro- 1124 4H- 1,2,4-triazol-4- yl)phenyl)ethynyl)- 1 - oxoisoindolin-2-yl)-N- methylbenzamideDB1 / 166057797.1Docket No. 133447-5010-WO3-(7-((4-(3-(2- methoxyethoxy)-l-methyl-5- oxo- 1, 5 -dihy dro-4H- 1,2,4- 1125 ztriazol-4-yl)phenyl)ethynyl)- l-oxoisoindolin-2-yl)-N- methylbenzamide? / II O \ / — N o z—o-J3-(7-((4-(3-(2- / / W ’I N— <z7 - = - ( / \=\ / > (dimethylamino)ethoxy)- 1 - ^ ^=7 W methyl-5-oxo-l,5-dihydro- 1126 4H-l,2,4-triazol-4-0 0yl)phenyl)ethynyl)- 1 - oxoisoindolin-2-yl)-N- methylbenzamide OyC)^NH^OHN^X / \ / I N — (z x =\) - = - (\ / > 3-(7-((4-(3-(2- hydroxy ethoxy)- 1 -methyl-5- oxo- 1, 5 -dihy dro-4H- 1,2,4- 1127 H0° triazol-4-yl)phenyl)ethynyl)- l-oxoisoindolin-2-yl)-N- methylbenzamide °Y(5^NHDB1 / 166057797.1Docket No. 133447-5010-WON-methyl-m-[7-(2-{p-[3- (methoxymethyl)- 1 -methyl-5- oxo-l,5-dihydro-4H-l,2,4- 1128 \z- ^z z— triazol-4-yl]phenyl}ethynyl)- J V 1 -oxo-2- isoindolinyl]benzamide 6 / II O \ / ^N\ II O \oI N— / =\ o / ) - = - ( fz / \x> N-methyl-m-{7-[2-(p-{3- [(dimethylamino)methyl]-l- methyl-5-oxo-l,5-dihydro- 1129 °0<4H-l,2,4-triazol-4- yl }phenyl)ethynyl]- 1 -oxo-2- isoindolinyl}benzamide ^NHXo CF3N^A / =\ / / \ 3-(4-((4-(3 -methoxy- 1 - \=7 methyl-5-oxo-l,5-dihydro- 4H-l,2,4-triazol-4- 11300=ZA yl)phenyl)ethynyl)- 1,1- dimethyl-3-oxo-6- (trifluoromethyl)isoindolin-2- yl)-N-methylbenzamide ^. NH3-(4-((4-(l,3-dimethyl-5-oxo- 1, 5-dihydro-4H- 1,2,4-triazol- 4-yl)phenyl)ethynyl)- 1,1- 1131dimethyl-3-oxo-6- (trifluoromethyl)isoindolin-2- yl)-N-methylbenzamideDB1 / 166057797.1Docket No. 133447-5010-WO3-(4-((4-(3 -methoxy- 1 - methyl-5-oxo-l,5-dihydro- 4H-l,2,4-triazol-4- 1132 y l)phenyl)ethynyl)- 1,1- dimethyl-3-oxo-6- (trifluoromethyl)isoindolin-2- yl)benzamide2-(3-(lH-imidazol-2- o yl)phenyl)-7-((4-(3-methoxy- 1 ° II V ° 1 -m ethyl - 5 -oxo- 1, 5 -di hy dro- 4H- 1,2,4-triazol-4- 1133yl)pheny l)ethynyl)-3,3 - dimethyl-5- (trifluoromethyl)isoindolin- 1 - one\z Z— / / CF3N^\ / =\ / \I N— (\ / ) - = - (z x> 3 -(4-((4-( 1, 3 -dimethyl-5 -oxo- W 1, 5-dihydro-4H- 1,2,4-triazol- 4-yl)phenyl)ethynyl)- 1,1- 1134dimethyl-3 -oxo-6- (trifluoromethyl)isoindolin-2- yl)benzamide °J6NH2 / / CF3N^A / =\ / / \ 2-(3-(lH-imidazol-2- 1 N— (\ / ) - = - (z x> yl)phenyl)-7-((4-(l,3- W di m ethyl - 5-oxo-l,5-di hydro- 4H-l,2,4-triazol-4- 11350y l)phenyl)ethynyl)-3,3 - dimethyl-5-Hf j (trifluoromethyl)isoindolin- 1 - oneDB1 / 166057797.1Docket No. 133447-5010-WO0N |X N~ ( AzAx) - = - < ^zAx>7-((4-(l,3-dimethyl-5-oxo- 1, 5 -dihydro-4H- 1,2,4-triazol- 1136 _ J — \4-yl)phenyl)ethynyl)-2- (pyridin-2-yl)isoindolin- 1 -oned^ 0°"° 7-((4-(l,3-dimethyl-5-oxo- o 1, 5 -dihydro-4H- 1,2,4-triazol- 4-yl)phenyl)ethynyl)-2-(3-(4- 1137hydroxy-4-methylpiperidine- l-carbonyl)phenyl)isoindolin- 1-oneZ z—0A |^. N— ( ZzAx) - = - < ^zAx)N^ / \ / \ — / (S)-7-((4-(l,3-dimethyl-5- oxo- 1,5 -dihydro-4H- 1,2,4- triazol-4-yl)phenyl)ethynyl)- 1138 2-(3 -(3 -hydroxy-3 - methylpiperidine- 1 - IX0carbonyl)phenyl)isoindolin- 1 - oner k\j^U-OHDB1 / 166057797.1Docket No. 133447-5010-WOO A IX N— ( ^zAx) - = - <z x)N^ / J — \ 2-(3-((37?,45)-3,4- dihydroxypyrrolidine-1- carbonyl)phenyl)-7-((4-( 1,3- 1139 di m ethyl - 5 -oxo- 1, 5 -di hydro- 477- 1,2,4-triazol-4- GV yl)phenyl)ethynyl)isoindolin- 1-one0XOH0A |X N— C AAx) — = — ( rzx 7Ni=7-((4-( 1,3 -dimethyl-5-oxo- \ \ J — \ 1, 5 -dihydro-4H- 1,2,4-triazol- 4-yl)phenyl)ethynyl)-2-(3- 1140 ((25,47?)-4-hydroxy-2- (hydroxymethyl)pyrrolidine- cv 1 -carbonyl)phenyl)i soindolin- 1-one\J0HHO< R>^NH0 AA 1X N~ ( AzAxV) - = - (z x) 3-(5-(azetidin-3-yl)-7-((4-N^ / \ / \ — / (l,3-dimethyl-5-oxo-l,5- dihydro-4H-l,2,4-triazol-4- 1141yl)phenyl)ethynyl)- 1 - oxoisoindolin-2-yl)-7V- methylbenzamide LV HN^DB1 / 166057797.1Docket No. 133447-5010-WOHN N— C 7 — \ / . N-methyl-3-(1-oxo-7-((4-(2-oxopiperazin-1- 1142yl)phenyl)ethynyl)isoindolin-2-yl)benzamideHN^3-(7-((4-bromophenyl)ethynyl)-1-oxoisoindolin-2-yl)-N-methylbenzamide01A coIX N— ( AZA 7 — = — < ^zA 7N-(3-(7-((4-(1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl)ethynyl)- 11441-oxoisoindolin-2-yl)phenyl)methanesulfonamide1o=s=o10 FI N — ( AZA 7 — = — ( Hz7\ / \ / 3-(4-((4-(1-ethyl-3-methoxy-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl)ethynyl)- 11456-fluoro-1,1-dimethyl-3-oxoisoindolin-2-yl)-N-methylbenzamideDB1 / 166057797.1Docket No. 133447-5010-WO 0H2N— — x n —6-((2-(3-(methylcarbamoyl)phenyl)-3-oxoisoindolin-4-yl)ethynyl)- 11461,2,3,4-tetrahydroisoquinoline-1-carboxamide- 0 HN^3-(7-((4-(3,5-dioxo-1,2,4-triazolidin-4-yl)phenyl)ethynyl)-1-oxoisoindolin-2-yl)-N-methylbenzamidez.z— - i iN-methyl-3-(1-oxo-7-((4-(2-oxoazetidin-1- 1148yl)phenyl)ethynyl)isoindolin-2-yl)benzamideN-methyl-3-(7-((4-(4-methyl-2-oxomorpholin-3- 1149yl)phenyl)ethynyl)-1-oxoisoindolin-2-yl)benzamideDB1 / 166057797.1Docket No. 133447-5010-WO3-(7-((4-(4- hydroxypyrrolidin-3- 1150 yl)phenyl)ethynyl)- 1 - oxoisoindolin-2-yl)-iV- methylbenzamideO Q QA<AX AA AAN i^ / N— < \Z / y — = — 11 <z1 o' \ — ° / y3-(7-((4-(1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl)ethynyl)-1-oxoisoindolin-2-yl)-N,N-dimethylbenzamide1 I^ / O. A AN\0N X z ' — MX X AA AA7-((4-(l,3-dimethyl-5-oxo- j — (1, 5 -dihydro-4H-1,2,4-triazol- 11524-yl)phenyl)ethynyl)-2-(1H-indol-3-yl)isoindolin-1-oneN-(4-((2-(3-(methylcarbamoyl)phenyl)-3-oxoisoindolin-4-yl)ethynyl)phenyl)-1H-imidazole-4-carboxamideDB1 / 166057797.1Docket No. 133447-5010-WO3-(7-((4-(1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)-3- 1154isopropylphenyl)ethynyl)-5-fluoro-1-oxoisoindolin-2-yl)benzamideO Fi N — < rZ\ y — = — <zy3-(7-((4-(1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)-3- 1155methylphenyl)ethynyl)-5-fluoro-1-oxoisoindolin-2-yl)-N-methylbenzamideHN^O F^■z~i N — <Zy — = — (zy3-(7-((4-(1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)-3- 1156(methylsulfonyl)phenyl)ethynyl)-5-fluoro-1-oxoisoindolin-2-yl)-N-methylbenzamideO F N IX N — < AZA > — — —Y (zX y3-(7-((3-cyano-4-(1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4- 1157yl)phenyl)ethynyl)-5-fluoro-1-oxoisoindolin-2-yl)-N-methylbenzamideHN^DB1 / 166057797.1Docket No. 133447-5010-WON-(azetidin-3-yl)-3-(7-((4-(1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl)ethynyl)-5-fluoro-1-oxoisoindolin-2-yl)benzamideW 'I I o3-(5-fluoro-7-((2-methyl-l- oxo- 1, 2,4,5 -tetrahydro- [ 1,2,4]triazolo[4,3 -aQquinolin- 1159 A ‘m7-yl)ethynyl)-1-oxoisoindolin-2-yl)-N-methylbenzamideY0-A AAi N — C y — = — < rzx y4-(7-((4-(1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl)ethynyl)-1-oxoisoindolin-2-yl)picolinamideN NH20i NA y — = — \ y3-(7-((4-(1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl)ethynyl)-1-oxoisoindolin-2-yl)-4-methylbenzamideNH2DB1 / 166057797.1Docket No. 133447-5010-WO0AX ^Ai N— y — = — (zy3-(7-((4-(1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)-3- 1162((dimethylamino)methyl)phenyl)ethynyl)-1-oxoisoindolin-yl)ethynyl)-1-oxoisoindolin-2-yl)-N-methylbenzamideHN^0A I-X N— < AZA ^Ay — = — (zy 3-(7-((4-(3-((2,7- II o 11x°diazaspiro[3.5]nonan-2- y l)methy 1)- 1 -methy 1-5 -oxo- 1163r? °^y 1, 5 -di hydro-4 / / - 1,2,4-triazol- 4-yl)phenyl)ethynyl)-l- oxoisoindolin-2-yl)-7V- HN-V °yXj methylbenzamide \ / / z z I— ^NHz l —I3-(7-((4-(3-((2,6-diazaspiro[3.3]heptan-2-yl)methyl)-1-methyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl)ethynyl)-1-oxoisoindolin-2-yl)-N-methylbenzamide0A IX N— <Zy — = — < ^zA yN^ / 3-(1-(aminomethyl)-4-((4-(1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4- 1165yl)phenyl)ethynyl)-3-oxoisoindolin-2-yl)-N-methylbenzamideDB1 / 166057797.1Docket No. 133447-5010-WO 0 / =\I N — <\ / ) - = - (z x>3-(4-((4-(1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl)ethynyl)-1-((2- 1166methoxyethyl)amino)-3-oxoisoindolin-2-yl)-N-methylbenzamide0NX / =\i N — (\ / ) — = — (zy7-((4-(1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl)ethynyl)-2-(3- 1167(2,2,2-trifluoro-1-(methylamino)ethyl)phenyl)isoindolin-1-oneF3-(7-((3,5-dimethyl-2-oxo-2,3-dihydro-1H-benzo[e][1,2,4]triazepin-7- 1168yl)ethynyl)-5-fluoro-1-oxoisoindolin-2-yl)-N-methylbenzamideHN^O F NX / =\ HI N — / > - = - <zV3-(7-((4-(1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)-2- 1169(methylsulfonyl)phenyl)ethynyl)-5-fluoro-1-oxoisoindolin-2-yl)benzamideNH2DB1 / 166057797.1Docket No. 133447-5010-WO 0 FNX / =\ HI N— (\ / > - = - <z x>3-(7-((4-(1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)-2- 1170(methylsulfonyl)phenyl)ethynyl)-5-fluoro-1-oxoisoindolin-2-yl)-N-methylbenzamide0y-X / =\ / r~\ I N — / ) - = - <z X>4-cyano-3-(7-((4-(1,3-dimethyl-5-oxo-1,5-dihydro-1171 4H-1,2,4-triazol-4-yl)phenyl)ethynyl)-1-oxoisoindolin-2-yl)benzamidevMNH2n1_N=X / / \ f / \ I N— <z x) - = - (z x>2-(3-(1H-imidazol-2-yl)phenyl)-7-((4-(1-(azetidin-3-ylmethyl)-3-methyl-5-oxo- 11721,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl)ethynyl)-3,3-dimethylisoindolin-1-oneNH3-(7-((5-(1,3-dimethyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)-1H-pyrazol-3-yl)ethynyl)-1-oxoisoindolin-2-yl)-N-methylbenzamideDB1 / 166057797.1Docket No. 133447-5010-WO 0i N— <Z— = — (zy2-(3-(4,5-dihydro-1H-imidazol-2-yl)phenyl)-7-((4-(3-methoxy-1-methyl-5-oxo- 11741,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl)ethynyl)-3,3-dimethylisoindolin-1-oney Z - 0I N— (zy — = — (zy 2-(3 -(4, 5 -dihydro- 1 H-NC5\ _ o QCO^J _z(L- imidazol-2-yl)phenyl)-7-((4- (l,3-dimethyl-5-oxo-l,5- 1175dihydro-4H-1,2,4-triazol-4- y l)pheny l)ethynyl )-3,3 - dimethylisoindolin- 1 -one i1^Y HN^Ny>Z z—3-(1-(azetidin-3-ylmethyl)-4-((4-(3-methoxy-1-methyl-5-oxo-1,5-dihydro-4H-1,2,4- 1176triazol-4-yl)phenyl)ethynyl)-1-methyl-3-oxoisoindolin-2-yl)benzamideO3-(1-(2-hydroxyethyl)-4-((4-(3-methoxy-1-methyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol- 1177 4-yl)phenyl)ethynyl)-1-methyl-3-oxoisoindolin-2-yl)benzamideNH2DB1 / 166057797.1Docket No. 133447-5010-WO3-(1-(cyanomethyl)-4-((4-(3-methoxy-1-methyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4- 1178yl)phenyl)ethynyl)-1-methyl-3-oxoisoindolin-2-yl)benzamideIz —0NX ^Ai N— e y — = — <\ _ / QCO \z_z^ y / , 3-(1-ethyl-4-((4-(3-methoxy-1-methyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4- 1179yl)phenyl)ethynyl)-1-methyl-3-oxoisoindolin-2-yl)benzamide? cNH2^r\ °°zZ z Z z——3-(4-((4-(3-methoxy-1-methyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4- 1180yl)phenyl)ethynyl)-1-methyl-1-(oxetan-3-ylmethyl)-3-oxoisoindolin-2-yl)benzamideO3-(1-(2-(dimethylamino)ethyl)-4-((4-(3-methoxy-1-methyl-5-oxo- 1181 1,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl)ethynyl)-1-methyl-3-oxoisoindolin-2-yl)benzamideNH2DB1 / 166057797.1Docket No. 133447-5010-WO0N IX N — < ^ZA y — = — ( ^zA yN^ / \ _ / \ _ / 3 -( 1, 1 -dimethy 1 -4 -((4 - ( 1 - methyl-3-(oxetan-3-yloxy)-5- oxo-1,5-dihydro-4H-l,2,4- 1182triazol-4-yl)phenyl)ethynyl)- 3 -oxoisoindolin-2- o—1XXyl)benzamide CLoNH20NX ^AI NX y — = — <zy^ Oc 3 -( 1 -(hy droxymethy 1 ) -4- ((4 - N<=^ w \= / OHo (3 -methoxy- 1 -methyl-5 -oxo- 1, 5 -dihydro-4H-1,2,4-triazol- / ° °AA 11834-yl)phenyl)ethynyl)-1-methyl-3-oxoisoindolin-2-yl)benzamide ^Y°NH2^\ O / AZY \ / / 7z-3 -( 1, 1 -dimethyl-4-((4-(l - methyl-3-((l-methylazetidin- 3 -yl)oxy)-5 -oxo- 1, 5 -dihydro- 11844H-1,2,4-triazol-4- yl)phenyl)ethy nyl)-3 - oxoisoindolin-2-yl)benzamideoAX AA ^A I N — <Zy — = — <zy 3 -(4-((4-(3 -cyclopropoxy- 1 - N^ / \ _ / \ _ / methyl-5-oxo-l,5-dihydro- 4H- 1,2,4-triazol-4- 1185 °XAyl)phenyl)ethynyl)- 1,1- dimethyl-3-oxoisoindolin-2- yl)benzamide (^XoNH2DB1 / 166057797.1Docket No. 133447-5010-WO3-(4-((4-(3-ethyl-l-methyl-5- oxo- 1,5 -di hydro-477- 1,2,4- 1186 triazol-4-yl)phenyl)ethynyl)- 1, 1 -dimethyl-3 -oxoi soindolin- 2-yl)benzamide 6oNX ^A| N — <zy - = - o <z x>\ _ / \ _ / 3-(4-((4-(3 -cyclopropyl- 1 - methyl-5-oxo-l,5-dihydro- 477- 1,2,4-triazol-4- 1187yl)phenyl)ethynyl)- 1,1- dimethyl-3-oxoisoindolin-2- Q ro yl)benzamide NH2O Fi N — <Z— — — (zy\ / \ — / 3-(4-((4-(3-ethyl-l-methyl-5- oxo- 1,5 -dihydro-4H-1,2,4- 1188 / triazol-4-yl)phenyl)ethynyl)- 6-fluoro-l,l-dimethyl-3- oxoisoindolin-2-yl)benzamide (^roNH2O F I N — (Zy — = — <zyNy / \ _ / \ _ / 3-(4-((4-(3 -cyclopropyl- 1 - methyl-5-oxo-l,5-dihydro- 477- 1,2,4-triazol-4- 1189yl)phenyl)ethynyl)-6-fluoro- 1, 1 -dimethyl-3 -oxoi soindolin- 2-yl)benzamideNH2DB1 / 166057797.1Docket No. 133447-5010-WO0AX AA I N — <z x> - = - (z x>N^ / \ _ / \ _ / 3 -(4-((4-(3 -chloro- 1-methyl- 5-oxo- 1, 5 -di hydro-4 / / - 1,2,4- 1190CloXX triazol-4-yl)phenyl)ethynyl)- 1, 1 -dimethyl-3 -oxoi soindolin- 2-yl)benzamide ^ >0NH20A IX N— ( AzAx> - = - <z x>N^ / \ _ / \ _ / 3 -(4-((4-(3 -methoxy- 1 - methyl-5-oxo- 1, 5-dihy dro- 4H- 1,2,4-triazol-4- 1191 / Oyl)phenyl)ethynyl)- 1 -methyl- 1 -(2-morpholinoethyl)-3 - oxoisoindolin-2-yl)benzamide X oNH21192 enantiomer 1 of compound 1177 * —1193 enantiomer 2 of compound 1177 * —O A IX N^z x) - = - < AzAx)\ _ / \ _ / 2-(3-(17 / -pyrazol-5- yl)phenyl)-7-((4-(3-methoxy- 1 -methyl - 5 -oxo- 1, 5 -dihy dro- 1194 / ° °AX4H- 1,2,4-triazol-4- y l)phenyl)ethynyl)-3,3 - dimethylisoindolin- 1 -one f lHL?0A IX N— ( AzAx) - = - ( AzAx)\ _ / \ _ / 2-(3-(l / / -pyrrol-2-yl)phenyl)- 7-((4-(3-methoxy-l-methyl-5- 1195 oxo- 1,5-di hydro-4 / / - 1,2,4- triazol-4-yl)phenyl)ethynyl)- 3,3 -dimethyli soindolin- 1 -oneX - —1196 enantiomer 1 of compound 1180 *DB1 / 166057797.1Docket No. 133447-5010-WO 1197 enantiomer 2 of compound 1180 * —O A IX N—x) - = - < ZzA V 2-(3-(4-((4-(3-methoxy-l- \ _ / \ _ / methyl-5-oxo-l,5-dihydro- 4 / f-l,2,4-triazol-4- 1198 / ° o'Ar V y l)phenyl)ethyny 1)- 1,1- dimethyl-3-oxoisoindolin-2- yl)phenyl)-7 / / -imidazole-4- OM C carboxamide H2N V^NHO AX ZA I N— (z9 - = - (z x)N^ / \ _ / \ _ / 7-((4-(3-methoxy-l-methyl-5- oxo- 1,5 -di hydro-47 / - 1,2,4- / ° o-Q\ triazol-4-yl)phenyl)ethynyl)- 1199 3, 3 -dimethyl -2-(3 -(4- (morpholine-4-carbonyl)- 1H- imidazol-2- yl)phenyl)isoindolin- 1 -one \ / Vn / Z^N X^-NHK / '-zz-O-~ZO F A IX N~ ( ZzAx) — = — ( ZzX >N^ / \ _ / \ _ / 3 -(6-fluoro- 1, 1 -dimethyl-4- ((4-(l-methyl-3-(oxetan-3- yloxy)-5 -oxo- 1, 5 -dihy dro- 12004H- 1,2,4-triazol-4- cY xY, yl)phenyl)ethynyl)-3- oxoisoindolin-2-yl)benzamide Cu°NH23 -(6-fluoro- 1, 1 -dimethyl-4- ((4-(l-methyl-3-((l- m ethyl azeti di n-3 -y 1 )oxy ) -5 - 1201 oxo- 1,5 -dihydro-4H-1,2,4- triazol-4-yl)phenyl)ethynyl)- 3-oxoisoindolin-2-yl)benzamideDB1 / 166057797.1Docket No. 133447-5010-WO0 FAX AA Hi N— <Zy — = — <zyN^ / \ / \ / 3 -(4-((4-(3 -cyclopropoxy- 1 - methyl-5-oxo-l,5-dihydro- 477-1,2,4-triazol-4- 1202 ^ / ° ° ti Vyl)phenyl)ethynyl)-6-fluoro- 1, 1 -dimethyl-3 -oxoisoindolin- 2-yl)benzamide NH2O F A IX N — < AZA y — = — < Hzy\ _ / \ _ / 3-(4-((4-(3-chloro-l-methyl- 5-oxo- 1, 5 -di hydro-477- 1,2,4- 1203CloXA triazol-4-yl)phenyl)ethynyl)- 6-fluoro-l,l-dimethyl-3- oxoisoindolin-2-yl)benzamide 6yNH20AX ^A AAI N — (Zy — = — (zy 3 -(4-((4-(3 -methoxy- 1 - N^ / \ _ / \ _ / methyl-5-oxo-l,5-dihydro- 477- 1,2,4-triazol-4- 1204 / ° yl)phenyl)ethynyl)- 1 -methyl- 3 -oxo- 1 -(2-(piperazin- 1 - yl)ethyl)isoindolin-2- odd o yl)benzamide1 HNH21205 enantiomer 1 of compound 1178 * —1206 enantiomer 2 of compound 1178 * —O A I-X AAN— (Zy — = — < AzA yN^ / \ _ / \ _ / 2-(3 -( 177- 1,2,4-triazol-5- yl)phenyl)-7-((4-(3-methoxy- 1 -methyl - 5 -oxo- 1, 5 -dihy dro- 1207 / °4H- 1,2,4-triazol-4- y l)pheny l)ethynyl )-3,3 - dimethylisoindolin- 1 -one d'vNDB1 / 166057797.1Docket No. 133447-5010-WO0A IX N — <Zy — = — < ^zA y2-(3 -(4-(azetidine- 1 - carbonyl)- l / / -imidazol-2- yl)phenyl)-7-((4-(3-methoxy- 1208 1 -m ethyl - 5 -oxo- 1, 5 -di hy dro- 477- 1,2,4-triazol-4- y l)pheny l)ethynyl )-3,3 - dimethylisoindolin- 1 -one A^NH0AX AA ^A I N — <Zy — = — (zyN^ / \ / \ / 2-(3 -(4-(hy droxy methyl)- 177- imidazol-2-yl)phenyl)-7-((4- (3 -methoxy- l-methyl-5 -oxo- / ° 12091, 5 -dihydro-4H-1,2,4-triazol- 4-yl)phenyl)ethynyl)-3,3- dimethylisoindolin- 1 -oneH( / ^NH0AX AA ^A I N— (Zy — = — (zyN^ / \ _ / \ _ / 7-((4-(3 -methoxy- 1 -methyl-5- oxo- 1, 5 -dihydro-4H-1,2,4- / ° QAA triazol-4-yl)phenyl)ethynyl)- 12103,3 -dimethyl-2-(3 -(8 -oxo- 2,5,7-triazaspiro[3.4]oct-5-en- 6-yl)phenyl)isoindolin- 1 -one / \ NJUHNA iV-NHO0 ClAX Hi N— (Zy — = — <zy 3-(6-chloro-4-((4-(3- \ _ / \ _ / methoxy- 1 -methyl-5-oxo-l,5- dihydro-4H-1,2,4-triazol-4- / ° 1211y l)phenyl)ethyny 1)- 1,1- dimethyl-3-oxoisoindolin-2-yl)benzamideDB1 / 166057797.1Docket No. 133447-5010-WO 0 \)i N— ( \Z_ / 7 — = — ( \z_ / 7 3-(6-methoxy-4-((4-(3- methoxy- 1 -methyl -5 -oxo- 1,5- dihydro-4H-1,2,4-triazol-4- 1212 / ° yl)phenyl)ethynyl)- 1,1- dimethyl-3-oxoisoindolin-2-yl)benzamide0 / NX ^A AN Iy / N — < \Z_ / 7 — = — < \z_ / 7 3-(6-cyano-4-((4-(3-methoxy- 1 -methyl - 5 -oxo- 1, 5 -di hy dro- 4H- 1,2,4-triazol-4- 1213 / ° yl)phenyl)ethynyl)- 1,1- dimethyl-3-oxoisoindolin-2-yl)benzamideo r-NX AN Iy / N— ( \Z_ / 7 — — — < \z_ / 7 3-(6-cyclopropyl-4-((4-(3- methoxy- 1 -methyl-5-oxo- 1,5- dihydro-4H-1,2,4-triazol-4- 1214 / ° y l)phenyl)ethynyl)- 1,1- dimethyl-3-oxoisoindolin-2- (^yO yl)benzamide NH2O / NX ^A AN Iiy / NX \Z / 7 — — — ( \z / 7 3 -(4-((4-(3 -methoxy- 1 - methyl-5-oxo-l,5-dihydro-4H-1,2,4-triazol-4- 1215 / °os:::O^ yl)phenyl)ethynyl)- 1,1,6- trimethyl-3-oxoisoindolin-2- yl)benzamideNH2DB1 / 166057797.1Docket No. 133447-5010-WOO \l —NX ^A HI N — <Z7 — = — <z7 3 -(6-(dimethylamino)-4-((4- \ / \ / (3 -methoxy- 1 -methyl -5-oxo- 1, 5 -dihydro-4H-1,2,4-triazol- 1216 z° ° 4-yl)phenyl)ethynyl)- 1,1- dimethyl-3-oxoisoindolin-2- yl)benzamide (L oNH2o" NX _ ^AN^ / N~~\ _ / \ _ / ^-OH 3 -( 1 -(2-hy droxy ethy 1 ) -4 - ((4 - (3 -methoxy- 1 -methyl-5 -oxo- 1, 5 -dihydro-4H-1,2,4-triazol- 1217 z°4-yl)phenyl)ethynyl)-l- methy 1-3 -oxoi soindolin-2-yl)- fibo Az-methylbenzamide HN^0N^ / \ _ / \ _ / <^OH? / -(l-cyclopropyl-177- pyrazol-3 -y 1 ) -3 -( 1 -(2- hy droxy ethy l)-4-((4-(3 - / °methoxy- 1 -methyl-5 -oxo- 1,5- 1218dihydro-4H-l,2,4-triazol-4- yl)phenyl)ethynyl)- 1 -methyl- oyd 3-oxoisoindolin-2-yl)benzamide. N^ / NH— NZjoNXi N— (Z7 — = — <z7 7-((4-(3-methoxy-l-methyl-5- N^ / \ / \ — / oxo- 1,5 -dihydro-4H-1,2,4- triazol-4-yl)phenyl)ethynyl)- 1219 z° 3,3-dimethyl-2-(3-(4- (trifluorom ethyl)- 177- imidazol-2- yl)phenyl)i soindolin- 1 -one NJ6F3C-A( 1VNHDB1 / 166057797.1Docket No. 133447-5010-WO 0N iX N— AA y — = — < AzA y 2-(3-(4- \ / \ — / ((dimethylamino)methyl)-17 / - imidazol-2-yl)phenyl)-7-((4- 1220 (3 -methoxy- 1 -methyl-5 -oxo- 1, 5 -dihydro-4H-1,2,4-triazol- 4-yl)phenyl)ethynyl)-3,3- dimethylisoindolin- 1 -one V-NH0A IX N — < AZA y — = — < AzA y\ _ / \ _ / 6-(3-(4-((4-(3-methoxy-l- methyl-5-oxo-l,5-dihydro- 4H- 1,2,4-triazol-4- 1221 / ° °AA yl)phenyl)ethynyl)- 1,1- dimethyl-3-oxoisoindolin-2- yl)phenyl)-2-oxa-5,7- diazaspiro[3.4]oct-5-en-8-one °\ V IO0i N — < ZZ~A y — = — ( AzA yN=s^ / \ / \ / 1 -(3 -(4-((4-(3-m ethoxy- 1 - methyl-5-oxo-l,5-dihydro- / ° 4H-1,2,4-triazol-4- 1222 y l)phenyl)ethynyl)- 1,1- dimethyl-3-oxoisoindolin-2- O X llXNXJ yl)phenyl)- 1,2,4-triazolidine- 3, 5-dioneHN |rNHoon_ M 2-(3 -( l / / -imidazol-2- tU / \ _ / \ _ / ^-OH yl)phenyl)-3-(2- hydroxyethyl)-7-((4-(3- 1223 methoxy- 1 -methyl-5 -oxo- 1,5- dihydro-4H-1,2,4-triazol-4- yl)phenyl)ethynyl)-3 - methylisoindolin- 1 -oneHN-2^DB1 / 166057797.1Docket No. 133447-5010-WO O AXi N^7 y — = — <zyN^ / \ _ / \ _ / 2-(3-(4-(azetidin-3-ylmethyl)- l / / -imidazol-2-yl)phenyl)-7- ((4-(3-methoxy-l-methyl-5- 1224 / ° oxo- 1,5 -dihydro-47 / - 1,2,4- HN^ triazol-4-yl)phenyl)ethynyl)- 3,3 -dimethyli soindolin- 1 -one ^ ^0V-NHO AX AA 2-(3-(4-((4-(3-methoxy-l- i N — <Zy — = — <zy\ _ / \ _ / methyl-5-oxo-l,5-dihydro- 477- 1,2,4-triazol-4- 1225 / ° yl)phenyl)ethynyl)- 1,1- dimethyl-3-oxoisoindolin-2- yl)phenyl)-177-imidazole-5-H11 carbonitrileN^< Ty^NoAX AA I N- \ y — = — (zy 3 -( 1, 1 -bi s(hy droxymethyl)-4- \= / \= / OH((4-(3 -methoxy- 1 -methyl -5- oxo- 1,5 -di hydro-477- 1,2,4- z° nl / ° N V-OH 1226triazol-4-yl)phenyl)ethynyl)- 3-oxoisoindolin-2-yl)benzamideoAX AA ^AI rwzy — = — (zy 7-((4-(3 -methoxy- 1 -methyl-5- N^ / \ _ / \ _ / oxo- 1,5 -dihydro-4H-1,2,4- triazol-4-yl)phenyl)ethynyl)- 1227 / ° 2-(3-(3-oxo-2,3-dihydro-177- pyrazol-1- yl)phenyl)isoindolin-l-oneHJMlDB1 / 166057797.1Docket No. 133447-5010-WO 0i N — <Z X> — = — <Z X)N^ / \ _ / \ _ / 7-((4-(3-methoxy-1-methyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl)ethynyl)-3,3-dimethyl-2-(3-(4-(oxetan-3-ylmethyl)-1H-imidazol-2-yl)phenyl)isoindolin-1-one _ / V-NHo—^0I N— (z x) — = — <z x>\ _ / \ _ / 7-((4-(3-methoxy-l-methyl-5- oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl)ethynyl)-2-(3-(piperazin-2-yl)phenyl)isoindolin-1-oneM - H 3-(6-fluoro-l-(2- N^N\ _ / \ _ / < OH hy droxy ethyl)-4-((4-(3 - methoxy- 1 -methyl-5-oxo- 1,5- 1230 / ° O^\ / \ dihydro-4H-1,2,4-triazol-4- yl)phenyl)ethynyl)- 1 -methyl- 3-oxoisoindolin-2-yl)- / V- cx ° methylbenzamide HN^0 FI N— (z x> - = - (z x)N^ / \ _ / \ _ / 3-(6-fluoro-l-(2- hy droxy ethyl)-4-((4-(3 - 7°1231 OXA^OH methoxy- 1 -methyl-5-oxo- 1,5- dihydro-4H-1,2,4-triazol-4- yl)phenyl)ethynyl)-3- oxoisoindolin-2-yl)benzamideNH2DB1 / 166057797.1Docket No. 133447-5010-WO 0 F-NX AA HI N — (( y — = — y 3-(6-fluoro-l-(2- N^ / \ / \ / hy droxy ethy 1 )-4 - ( (4 - (3 - methoxy- 1 -methyl-5-oxo-l,5- 1232 7° dihydro-4H-1,2,4-triazol-4-yl)phenyl)ethynyl)-3-oxoisoindolin-2-yl)-N-methylbenzamide HN^O FN^ / NX, _ / \ _ / J— O 3-(6-fluoro-4-((4-(3-methoxy- 1 -m ethyl - 5 -oxo- 1, 5 -di hy dro- 4H-1,2,4-triazol-4-yl)phenyl)ethynyl)-1-(oxetan-3-ylmethyl)-3-oxoisoindolin-2-yl)benzamideNH2O FN<pN\ _ / \ _ / J— 0 3-(6-fluoro-4-((4-(3-methoxy- 1 -m ethyl - 5-oxo-l,5-dihy dro- 4H-1,2,4-triazol-4-yl)phenyl)ethynyl)-1-(oxetan-3-ylmethyl)-3-oxoisoindolin-2-yl)-N-methylbenzamideHN^0 FN1^ / N— \ \ / 7 — — \ \ / / I — M NUH 3 -( 1 -(azeti din-3 -ylmethyl)-6- fluoro-4-((4-(3 -methoxy- 1 - methyl-5-oxo- 1, 5-dihydro- 1235 / °4H-1,2,4-triazol-4-yl)phenyl)ethynyl)-3-oxoisoindolin-2-yl)benzamide HEIGHT="657" WIDTH="512" SRC="imgf000122_0001_table.tif" / > NH2DB1 / 166057797.1Docket No. 133447-5010-WO0 FNX AA 3-(l-(azetidin-3-ylmethyl)-6- N1^s / \ / 7 = \ \ / / | — M NUH fluoro-4-((4-(3 -methoxy- 1 - methyl-5-oxo-l,5-dihydro- 1236 / ° 4H-1,2,4-triazol-4-yl)phenyl)ethynyl)-3-oxoisoindolin-2-yl)-N-methylbenzamideNH20 FNX ^A HI N— (z x) - — - (z x>\ _ / \ _ / 3 -( 1 -ethy l-6-fluoro-4-((4-(3 - methoxy- 1 -methyl -5 -oxo- 1,5- dihydro-4H-1,2,4-triazol-4-yl)phenyl)ethynyl)-3-oxoisoindolin-2-yl)-N-methylbenzamideHN^O F A IX N — ( AzAx) - = - < Hz x>N^ / \ _ / \ _ / . N-( 1 -cy cl opropyl- \H- pyrazol-3 -yl )-3 -(1 -ethy 1-6- / ° fluoro-4-((4-(3 -methoxy- 1 - 1239 methyl-5-oxo-l,5-dihydro- 477- 1,2,4-triazol-4- yl)phenyl)ethynyl)-3- oy^oxoisoindolin-2-yl)benzamide N^ / NH— N JDB1 / 166057797.1Docket No. 133447-5010-WO3 -( 1 -ethy l-6-fluoro-4-((4-(3 - methoxy- 1 -methyl-5-oxo-l,5- dihydro-4H-1,2,4-triazol-4-yl)phenyl)ethynyl)-1-methyl-3-oxoisoindolin-2-yl)benzamidei N — <Zy — = — <zyN=^ / \ _ / \ _ / , 3 -( 1 -ethyl-6-fluoro-4-((4-(3 - o methoxy- 1 -methyl-5-oxo-l,5- dihydro-4H-1,2,4-triazol-4-yl)phenyl)ethynyl)-1-methyl-3-oxoisoindolin-2-yl)-N-methylbenzamide / Z z—Z2—jV-Q-cyclopropyl-l / / - pyrazol-3-yl)-3-(l-ethyl-6- fluoro-4-((4-(3 -methoxy- 1 - methyl-5-oxo- 1, 5-dihydro- 12424H-1,2,4-triazol-4-yl)phenyl)ethynyl)-1-methyl-3-oxoisoindolin-2-yl)benzamideO Fi N— (Zy — = — (zyN^ / \ _ / \ _ / , 3 -(4-((4-(3 -cyclopropoxy- 1 - methyl-5-oxo-l,5-dihydro- 4H-1,2,4-triazol-4-yl)phenyl)ethynyl)-1-ethyl-6-fluoro-1-methyl-3-oxoisoindolin-2-yl)benzamideNH2DB1 / 166057797.1Docket No. 133447-5010-WO0 FN IX N — < FZA y — = —H <zy, 3 -(6-fluoro- 1, 1 -dimethyl-4- \ _ / \ _ / ((4-(l-methyl-3-(oxetan-3- yloxy)-5 -oxo- 1, 5-dihydro- 1244 4H-1,2,4-triazol-4-yl)phenyl)ethynyl)-3-oxoisoindolin-2-yl)-N-methylbenzamideHN^0 FN IX N— ( FZA Hy — = — (zyN^ / \ _ / \ _ / 3 -(4-((4-(3 -cyclopropoxy- 1 - o methyl-5-oxo- 1, 5-dihydro- 4H-1,2,4-triazol-4-yl)phenyl)ethynyl)-6-fluoro-1,1-dimethyl-3-oxoisoindolin-2-yl)-N-methylbenzamideHN^o L3-(4-((4-(3-((2,2- dimethyloxetan-3 -yl)oxy)- 1 - methyl-5-oxo-l,5-dihydro- 1246 4H-1,2,4-triazol-4-yl)phenyl)ethynyl)-6-fluoro-1,1-dimethyl-3-oxoisoindolin-2-yl)benzamideNH2DB1 / 166057797.1Docket No. 133447-5010-WO0 Fi N— (' y — = — <zy 3 -(6-fluoro- 1, 1 -dimethyl-4- \ _ / \ _ / ((4-(l -methyl-3 -(oxetan-3 - ylmethoxy)-5-oxo-l,5- 1248 / z—z° dihydro-4H-1,2,4-triazol-4-yl)phenyl)ethynyl)-3-oxoisoindolin-2-yl)-N-methylbenzamide3 -(6-fluoro- 1, 1 -dimethyl-4- ((4-(l -methyl-3 -(oxetan-3 - ylmethoxy)-5-oxo-l,5- 1249dihydro-4H-1,2,4-triazol-4-yl)phenyl)ethynyl)-3-oxoisoindolin-2-yl)benzamide3 -(6-fluoro- 1, 1 -dimethyl-4- ((4-( 1 -methyl-3-( 1 -(oxetan-3 - yl)ethoxy)-5-oxo-l,5- 1250 dihydro-4H-1,2,4-triazol-4-yl)phenyl)ethynyl)-3-oxoisoindolin-2-yl)-N-methylbenzamide0 Fi N— <Zy — = — <zy 3 -(6-fluoro- 1, 1 -dimethyl-4- ((4-(l-methyl-3-((l- methylpiperidin-4-yl)oxy)-5- 1251 OAV oxo- 1,5-dihydro-4H- 1,2,4- triazol-4-yl)phenyl)ethynyl)-3-oxoisoindolin-2-yl)-N-methylbenzamideHN^DB1 / 166057797.1Docket No. 133447-5010-WO0 FNX AA H I N— ('x) - = - <z x) 3 -(6-fluoro- 1, 1 -dimethyl -4- \ _ / \ _ / ((4-( 1 -methyl-3 -(( 1 - methylpiperidin-4-yl)oxy)-5- 1252 oxo- 1,5-dihydro-47 / - 1,2,4- triazol-4-yl)phenyl)ethynyl)-3-oxoisoindolin-2-yl)benzamide0 FAX AA H 3 -(6-fluoro- 1, 1 -dimethyl-4- I N^AX) - = - <Z X) \ _ / \ _ / ((4-(l -methyl-3 -(( 1 - methylpyrrolidin-3-yl)oxy)-5- 1253 oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl)ethynyl)-3-oxoisoindolin-2-yl)-N-methylbenzamide0 FAX AA H I N — (z x) - = - (z x) 3 -( 1 -ethyl-6-fluoro- 1 -methyl - N^ / \ _ / \ _ / ,4-((4-( 1 -methyl-3 -(ox etan-3 - yloxy)-5 -oxo- 1, 5 -dihy dro- 1254 °AV 4H-1,2,4-triazol-4-yl)phenyl)ethynyl)-3-oxoisoindolin-2-yl)benzamide0 FAX AA H3 -( 1 -ethyl-6-fluoro- 1 -methyl- I N— (z x) - = - (z x)N^ / \ _ / \ _ / , 4-((4-( 1 -methyl-3 -(oxetan-3 - y loxy)-5 -oxo- 1, 5 -dihy dro- ^_ / °01255 4H-1,2,4-triazol-4-yl)phenyl)ethynyl)-3-oxoisoindolin-2-yl)-N-methylbenzamideHN^DB1 / 166057797.1Docket No. 133447-5010-WO3 -(4-((4-(3 -cyclopropoxy- 1 - methyl-5-oxo- 1, 5-dihy dro- 4H-1,2,4-triazol-4-yl)phenyl)ethynyl)-1-ethyl-6-fluoro-1-methyl-3-oxoisoindolin-2-yl)-N-methylbenzamide0 FxX Hi N — <Zy — = — (zy 3 -( 1 -ethyl-6-fluoro- 1 -methyl- \ _ / \ / , 4-((4-( 1 -methy 1-3 -(( 1 - methylpiperidin-4-yl)oxy)-5- 1257 oxo- 1,5 -di hydro-47 / - 1,2,4- triazol-4-yl)phenyl)ethynyl)-3-oxoisoindolin-2-yl)benzamideA / / \ / Z z—3 -( 1 -ethyl-6-fluoro- 1 -methyl - 4-((4-( 1 -methyl-3 -(( 1 - methylpiperidin-4-yl)oxy)-5- 1258 oxo- 1,5 -di hydro-47 / - 1,2,4- triazol-4-yl)phenyl)ethynyl)-3-oxoisoindolin-2-yl)-N-methylbenzamideO FxXi N — ( rZx y — = — ( Hzy 3 -( 1 -ethyl-6-fluoro- 1 -methyl - \ _ / \ _ / , 4-((4-( 1 -methyl-3 -(( 1 - methy lpyrrolidin-3 -yl)oxy)-5- 1259 oxo- 1,5-di hydro-47 / - 1,2,4- triazol-4-yl)phenyl)ethynyl)-3-oxoisoindolin-2-yl)benzamideNH2DB1 / 166057797.1Docket No. 133447-5010-WO3 -( 1 -ethyl -6-fluoro- 1 -m ethyl - 4-((4-( 1 -methyl-3 -(( 1 - methylpyrrolidin-3-yl)oxy)-5- 1260 oxo- 1,5-dihydro-4H- 1,2,4- triazol-4-yl)phenyl)ethynyl)-3-oxoisoindolin-2-yl)-N-methylbenzamideoA iX AAN^ / N — < \Z_ / X) — = — < \Z_ / X> 4-(3 -(7 -((4 - (3 -methoxy- 1 - methyl-5-oxo-l,5-dihydro- 4H-1,2,4-triazol-4-yl)phenyl)ethynyl)-1-oxoisoindolin-2-yl)phenyl)oxazolidin-2-oneo / zz-—I N— <z x> = <z x>N^ / \ / \ / 7-((4-(3 -methoxy- 1 -methyl-5- oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl)ethynyl)-2-(3-(2-oxoimidazolidin-4-yl)phenyl)isoindolin-1-oneHN^0 FAX AA H I N— <z x) - = - (z x>N^ / \ _ / \ _ / 7V-(1 -cyclopropyl- 1H- pyrazol-3 -y 1 )-3 -(6-fluoro- 1 - z° oXA^OH(2-hydroxyethyl)-4-((4-(3- 1263 methoxy- 1 -methyl-5-oxo-l,5- dihydro-4H-1,2,4-triazol-4- yl)pheny l)ethy nyl)-3 - °y6oxoisoindolin-2-yl)benzamide N^NHDB1 / 166057797.1Docket No. 133447-5010-WO O FN^N\ _ / \ _ / pO iV-(l-cyclopropyl-l / 7- pyrazol-3 -yl )-3 -(6-fluoro-4- / ° ((4-(3 -methoxy- 1 -methyl -5- 1264 oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl)ethynyl)-1-(oxetan-3-ylmethyl)-3-oxoisoindolin-2-yl)benzamide£> — NZjO F, AA HN1^s / \ / 7 — \ \ / / I — M NUH 3 -( 1 -(azeti din-3 -ylmethyl)-6- fluoro-4-((4-(3 -methoxy- 1 - methyl-5-oxo- 1, 5-dihy dro- / °O’SV^ / LJ4H-1,2,4-triazol-4-yl)phenyl)ethynyl)-3-oxoisoindolin-2-yl)-N-(1-cyclopropyl-1H-pyrazol-3-yl)benzamideb^N' jO F N IX N— ( ^ZAx) — = — ( Hz73 -( 1 -(cyanomethyl)-6-fluoro-NX r \ 4-((4-(3 -methoxy- 1 -methyl-5- oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl)ethynyl)-3-oxoisoindolin-2-yl)-N-methylbenzamide3-(6-fluoro-4-((4-(3-methoxy- 1 -methyl - 5 -oxo- 1, 5 -di hy dro- 4H-1,2,4-triazol-4-yl)phenyl)ethynyl)-1-methyl-3-oxoisoindolin-2-yl)benzamideDB1 / 166057797.1Docket No. 133447-5010-WO 0 FNX AA H| N—x) - = - (z x>\ _ / \ — / 3-(6-fluoro-4-((4-(3-methoxy- 1 -methyl - 5 -oxo- 1, 5 -dihy dro- 4H- 1,2,4-triazol-4- 1268yl)phenyl)ethynyl)- 1 -methyl- 3-oxoisoindolin-2-yl)-2V- methylbenzamide uvHN^0 FN-X AA HI N — <z x> - = - (z x>N^ / \ _ / \ _ / N-(1-cyclopropyl-1H-pyrazol-3-yl)-3-(6-fluoro-4- / ° ((4-(3 -methoxy- 1 -methyl -5- 1269 oxo- 1,5 -dihydro-4H-1,2,4- triazol-4-yl)phenyl)ethynyl)- 1-methyl-3-oxoisoindolin-2- yl)benzamide.yl)benzamide. N^ / NHD^NZI0 FNX AA H I N— (z x) - = - <z x>\ _ / \ _ / 2-(3 -( l / 7-imidazol-2- yl)phenyl)-5 -fluoro-7-((4-(3 - methoxy- 1 -methyl -5 -oxo- 1,5- 1270 / °dihydro-4H- 1,2,4-triazol-4- yl)phenyl)ethynyl)-3- methylisoindolin- 1 -one HN-^0 FXNX o _ H N3 -( 1 -(cyanomethyl)-6-fluoro- t^N\= / —W " 4-((4-(3 -methoxy- 1 -methyl-5- oxo- 1,5 -di hydro-477- 1,2,4- 1271triazol-4-yl)phenyl)ethynyl)-1-methyl-3-oxoisoindolin-2-yl)benzamide cb^oNH2DB1 / 166057797.1Docket No. 133447-5010-WO3 -( 1 -(cyanomethyl)-6-fluoro- 4-((4-(3-methoxy-l-methyl-5- oxo- 1,5-di hydro-477- 1,2,4- 1272triazol-4-yl)phenyl)ethynyl)- l-methyl-3-oxoisoindolin-2- yl)-N-methylbenzamide / O3 -( 1 -(cyanomethyl)-6-fluoro- o o11 ° 4-((4-(3 -methoxy- 1 -methyl-5- H11° oxo-1,5-dihydro-47 / -l,2,4- 1273 triazol-4-yl)phenyl)ethynyl)- l-methyl-3-oxoisoindolin-2-? A C yl)-N-(1-cyclopropyl-1H-pyrazol-3-yl)benzamide XVx° / Z z Z z—Z z——3-(6-fluoro-4-((4-(3-methoxy- 1 -m ethyl - 5 -oxo- 1, 5 -di hy dro- 4H-1,2,4-triazol-4- 1274yl)phenyl)ethynyl)-1-methyl-1-(oxetan-3-ylmethyl)-3-oxoisoindolin-2-yl)benzamide0 F\ / C <°\i N — ex) — = — <zy \ \ 3-(6-fluoro-4-((4-(3-methoxy- N^ / \ / \ / 1 -m ethyl - 5 -oxo- 1, 5 -di hy dro- 477-l,2,4-triazol-4- 7° oX^V1275 yl)phenyl)ethynyl)- 1 -methyl- 1 -(oxetan-3 -ylmethy l)-3 - oxoisoindolin-2-yl)-N-methylbenzamideDB1 / 166057797.1Docket No. 133447-5010-WO0 Fi N— (Zy — = — < y \ \N^ / \ _ / \ _ / N-(1-cyclopropyl-1H-pyrazol-3-yl)-3-(6-fluoro-4- / ° ((4-(3 -methoxy- 1 -methyl -5- oxo- 1,5 -dihydro-4H-1,2,4- 1276triazol-4-yl)phenyl)ethynyl)- 1 -methyl- 1 -(oxetan-3 - ylmethyl)-3 -oxoisoindolin-2- yl)benzamideZN^ / NHN' 2jO Fi N — <Zy — = — <zy 3 -(6-fluoro- 1, 1 -dimethyl-4- N=^ / \ _ / \ / ((4-( 1 -methyl-3 -(( 1 - methylazetidin-3-yl)oxy)-5- 1277 oxo- 1,5 -dihydro-4H-1,2,4- triazol-4-yl)phenyl)ethynyl)- 3-oxoisoindolin-2-yl)-N-methylbenzamide HN^O F" NX Ki N^Zy — = — (zy 3 -(6-fluoro- 1, 1 -dimethyl-4- N^ / \ _ / \ _ / ((4-(l -methyl-3 -((3- methyloxetan-3-yl)oxy)-5- 1278 oxo- 1,5 -dihydro-4H-1,2,4- °^ / JL triazol-4-yl)phenyl)ethynyl)- 3-oxoisoindolin-2-yl)-N-methylbenzamide HN^0 Fi N— (Zy — = — (zy 3 -(6-fluoro- 1, 1 -dimethyl-4- \ / \ — / ((4-(l-methyl-3-((3- methyloxetan-3-yl)oxy)-5- 1279 oxo- 1,5 -dihydro-4H-1,2,4- Ji triazol-4-yl)phenyl)ethynyl)- 3 -oxoisoindolin-2- Cu° yl)benzamideNH2DB1 / 166057797.1Docket No. 133447-5010-WO0 FI N — < 3-(4-((4-(3-((l,3- \Z_ / X> — = — ( \Z_ / X>dimethylazeti din-3 -yl)oxy)- 1 - methyl-5-oxo-l,5-dihydro- 1280 4H-1,2,4-triazol-4- -" N-V T yl)phenyl)ethynyl)-6-fluoro- 1, 1 -dimethyl-3 -oxoisoindolin- 2-yl)-N-methylbenzamide UToHN^0 FNX H3-(4-((4-(3-((l,3- I N— (z x> - = - (z x)\ _ / \ _ / dimethylazeti din-3 -yl)oxy)- 1 - methyl-5-oxo- 1, 5-dihydro- 1281 4 / f-l,2,4-triazol-4- yl)phenyl)ethynyl)-6-fluoro- 1, 1 -dimethyl-3 -oxoisoindolin- Cy 2-yl)benzamide NH20 F2-(3 -( l / / -imidazol-2- | N— (z x) - = - (z x) yl)phenyl)-5-fluoro-3,3- N^ / \ _ / \ _ / dimethyl-7-((4-(l-methyl-3- (oxetan-3-ylmethoxy)-5-oxo- 1282 / °1, 5-dihydro-4H-1,2,4-triazol- 4- yl)phenyl)ethynyl)isoindolin- X C^X^N 1-oneHN^O F| N — <z x) = - (z x)3 -(6-fluoro- 1, 1 -dimethyl-4- Ny' \ / \ / ((4-(l-methyl-3-(l-(oxetan-3- yl)ethoxy)-5-oxo-l,5- 1283dihydro-4H-1,2,4-triazol-4- yl)pheny l)ethy nyl)-3 - oxoisoindolin-2-yl)benzamide NH2DB1 / 166057797.1Docket No. 133447-5010-WO3 -(6-fluoro- 1, 1 -dimethyl -4- ((4-( 1 -methyl-3 -(( 1 - methylpyrrolidin-3-yl)oxy)-5- 12847?'I z zz —- oxo- 1,5-dihydro-4J7- 1,2,4- Lk J k- triazol-4-yl)phenyl)ethynyl)- 3-oxoisoindolin-2-yl)benzamide0 FN iX N— / Hy — = / o — <_zy 3 -( 1 -ethyl-6-fluoro- 1 -methyl- \ \ _ / , 4-((4-( 1 -methyl-3 -(( 1 - methylazetidin-3-yl)oxy)-5- 1285 ^7° oxo- 1,5 -dihydro-4H-1,2,4- triazol-4-yl)phenyl)ethynyl)- 3 -oxoi soindolin-2-zQ M ozCu yl)benzamide NH23 -( 1 -ethyl-6-fluoro- 1 -methyl - 4-((4-( 1 -methyl-3 -(( 1 - methylazeti din-3 -yl)oxy)-5- 1286 oxo- 1,5 -di hydro-477- 1,2,4- triazol-4-yl)phenyl)ethynyl)-3-oxoisoindolin-2-yl)-N-methylbenzamide0 FNX AN Hi N— e y — — — <zy 3 -( 1 -ethyl-6-fluoro- 1 -methyl- \ _ / \ _ / , 4-((4-(l-methyl-3-((2-methyl- 2-azaspiro[3.3]heptan-6- 1287 yl)oxy)-5-oxo-l,5-dihydro-4H-1,2,4-triazol-4- yl)phenyl)ethynyl)-3 - / N^ C^Y° oxoi soindolin-2-yl)benzamideNH2DB1 / 166057797.1Docket No. 133447-5010-WO 0 FNX ^A HI N— (z7 — = — <zV 3-(4-((4-(3-((l,3- N^ / \ _ / \ _ / , dimethylazeti din-3 -yl)oxy)- 1 - methyl-5-oxo-l,5-dihydro- 1288 4 / / - 1,2,4-triazol-4- yl)phenyl)ethynyl)- 1 -ethy 1-6- fluoro- 1 -methyl-3 - oxoisoindolin-2-yl)benzamide OyoNH20 F3-(4-((4-(3-((l,3- AX AA I N — (Zy — = — <zydimethylazetidin-3 -yl)oxy)- 1 - Ny / \ _ / \ _ / , ■o methyl-5-oxo- 1, 5-dihy dro- 477- 1,2,4-triazol-4- A V 1289yl)phenyl)ethyny 1)- 1 -ethy 1-6- fluoro- 1 -methyl-3 - oxoisoindolin-2-yl)-7V- CL.0 methylbenzamideHN^0 FZ z—NX H 2-(3 -( l / / -imidazol-2- I N— (Zy — — — (zyNy / \ _ / \ _ / yl)phenyl)-3-ethyl-5-fluoro-7- ((4-(3-methoxy-l-methyl-5- / ° 1290 oxo- 1,5-di hydro-4 / 7- 1,2,4- triazol-4- yl)phenyl)ethynyl)isoindolin- 1-one ^ rN>3 -(1 -cyclopropyl-6-fluoro-4- ((4-(3-methoxy-l-methyl-5- oxo- 1,5 -di hydro-477- 1,2,4- 1291triazol-4-yl)phenyl)ethynyl)- 3-oxoisoindolin-2-yl)benzamideDB1 / 166057797.1Docket No. 133447-5010-WO0 Fi N— (' y — = — (zy\ _ / \ _ / 3 -( 1 -cy cl opropyl-6-fluoro-4- ((4-(3 -methoxy- 1 -methyl -5- oxo- 1,5-di hydro-47 / - 1,2,4- 1292 7°triazol-4-yl)phenyl)ethynyl)-3-oxoisoindolin-2-yl)-N-methylbenzamide HN^3 -(6-fluoro-4-((4-(3 -methoxy- 1 -m ethyl - 5 -oxo- 1, 5 -di hy dro- o4H- 1,2,4-triazol-4- 1293yl)phenyl)ethynyl)-l-(2- methoxy ethyl)- 1 -methyl-3 - oxoisoindolin-2-yl)benzamide0 F / Z z—" N-X AA H / 3-(6-fluoro-4-((4-(3-methoxy- 1 -m ethyl - 5 -oxo- 1, 5 -di hy dro- 477-l,2,4-triazol-4- / ° o=5Ar \ 1294 yl)phenyl)ethy nyl)- 1 -(2- methoxy ethyl)- 1 -methyl-3 - oxoisoindolin-2-yl)-N-methylbenzamide HN^0 FXNX I i N — (Zy — = — <zy / 7V-(1 -cyclopropyl- \H- \ _ / \ _ / r^Opyrazol-3 -y 1 )-3 -(6-fluoro-4- ((4-(3-methoxy-l-methyl-5- oxo-1,5-dihydro-47f-l,2,4- 1295triazol-4-yl)phenyl)ethynyl)- 1 -(2-methoxy ethyl)- 1 -methyl - OyCj 3-oxoisoindolin-2-yl)benzamide N^ / NHL^-N jDB1 / 166057797.1Docket No. 133447-5010-WO0 FA iX AAN^ / N — < \( / X) — = — < H 2-(3 -( 1H-imidazol-2- \Z / >y l)pheny l)-5 -fluoro-3,3 - dimethyl-7-((4-(l -methyl-3- 1296 (oxetan-3 -yloxy )-5 -oxo- 1,5- dihydro-4H-1,2,4-triazol-4- yl)phenyl)ethynyl)isoindolin- 1-one O^NHN-^O F2-(3-(l / / -imidazol-2- A IX N— < AZAX) — = — < HZ X'N^- / \ _ / \ _ / > yl)phenyl)-5 -fluoro-3,3 - dimethyl-7-((4-(l -methyl-3- (( 1 -methylazeti din-3 -yl)oxy)- 12975-oxo- 1, 5 -di hydro-4 / / - 1,2,4- triazol-4- yl)phenyl)ethynyl)isoindolin-ZOYN 1-oneHN^0 F2-(3 -( lH-imidazol-2- AX K| N— (z X) - = - <z1 yl)pheny l)-5 -fluoro-3,3 - N^ / \ _ / \ _ / dimethyl-7-((4-(l-methyl-3- (( 1 -methylpiperidin-4- 1298 z^° < A / \yl)oxy)-5-oxo-l,5-dihydro- 4H-l,2,4-triazol-4- yl)phenyl)ethynyl)isoindolin- f i1-one HN^ / O F2-(3 -( l / / -imidazol-2- AX AA H| N— (Z x) — = — (z x> yl)phenyl)-5 -fluoro-3,3 - N^ / \ _ / \ _ / dimethyl-7-((4-(l-methyl-3- (( 1 -methylpyrrolidin-3 - 1299yl)oxy)-5 -oxo- 1,5 -dihydro- 4H- 1,2,4-triazol-4- A A yl)phenyl)ethynyl)isoindolin-1UyN 1-oneHN~A^DB1 / 166057797.1Docket No. 133447-5010-WO 0 FNX AA H I N— (Z X) — = — <Z X2-(3-(l / / -imidazol-2- N^ / \ _ / \ — / >, y l)phenyl)-3 -ethy 1-5 -fluoro-3 - methyl-7-((4-( 1 -methy 1-3 -(( 1 - — 1 methylpyrrolidin-3-yl)oxy)-5- 1300oxo- 1,5 -di hydro-477- 1,2,4- \ z z— 1triazol-4- cf A^^s>oozyl)phenyl)ethynyl)isoindolin-1Uy" 1-one HN^763-(l-ethyl-6-fluoro-l-methyl- 4-((4-( 1 -methyl-3 -((2-methyl- 2-azaspiro[3.3]heptan-6- yl )oxy)-5 -oxo- 1, 5 -dihydro- 13014H-1,2,4-triazol-4- yl)phenyl)ethynyl)-3- oxoisoindolin-2-yl)-7V- < -.Zo methylbenzamide 0 F2-(3-(l / 7-imidazol-2- N^N\_ / / ^OH yl)phenyl)-5 -fluoro-3 -(2- hydroxyethyl)-7-((4-(3- 1302 methoxy- 1 -methyl-5-oxo-l,5- z°QiS=O\dihydro-4H-l,2,4-triazol-4- yl)pheny l)ethy nyl)-3 - methylisoindolin-l-oneO F AX ^A X 2-(3-(177-imidazol-2- I N — <z x> - = - (z x)N^ / \ _ / \ _ / yl)phenyl)-5-fluoro-3-(2- hydroxyethyl)-7-((4-(3-ZO O / A / "™ 1303 methoxy-l-methyl-5-oxo-l,5- dihydro-4 / 7-l,2,4-triazol-4- yl)phenyl)ethynyl)isoindolin- 1-oneDB1 / 166057797.1Docket No. 133447-5010-WO0 FN^ / N\ _ / 2-(3 -( l / / -imidazol-2- \ _ / pOyl)phenyl)-5-fluoro-7-((4-(3- methoxy- 1 -methyl-5-oxo- 1,5- 1304 / °dihydro-4H-1,2,4-triazol-4- yl)phenyl)ethynyl)-3-(oxetan- 3 -y lmethyl)i soindolin- 1 -one2-(3 -( l / / -imidazol-2- yl)phenyl)-5 -fluoro-3,3 - dimethyl-7-((4-(l-methyl-3- I o ((3 -methyloxetan-3 -yl)oxy)- 13055-oxo- 1,5 -di hydro-47 / - 1,2,4- triazol-4- yl)phenyl)ethynyl)isoindolin- 1-oneO F AX AA 2-(3-(1H-imidazol-2- I N — <z x) - = - <z x>N^ / \ _ / \ _ / yl)phenyl)-7-((4-(3-((2,2- dimethyloxetan-3-yl)oxy)-l - 1306 methyl-5-oxo- 1, 5-dihy dro- o— U- 4H- 1,2,4-triazol-4- yl)phenyl )ethy nyl)-5 -fluoro- O^N 3,3 -dimethyli soindolin- 1 -one HN-A^O F AA H 2-(3 -( 177-imidazol-2- N Ip N— ( \z_ / x) - = - < \z_ / x> yl)phenyl)-7-((4-(3-((l,3- dimethylazeti din-3 -yl)oxy)- 1 - 1307 methyl-5-oxo-l,5-dihydro- p / o<s;O<N— ' A^A 47 / -l,2,4-triazol-4- yl)phenyl)ethynyl)-5-fluoro- 3,3 -dimethyli soindolin- 1 -onezCuHN-A^DB1 / 166057797.1Docket No. 133447-5010-WO0 FA 3 -(6-fluoro- 1, 1 -dimethyl-4- IX N — (z x) — = — < Hz x:>\ _ / \ _ / ((4-(l-methyl-3-((l- methylazeti din-3 - yl)methoxy)-5-oxo-l,5- 1308 z°dihydro-4H-1,2,4-triazol-4- yl)phenyl)ethynyl)-3- IL J.,o oxoisoindolin-2-yl)-iV- \ methylbenzamide HN^0 FI N— (z x> - = - (z x> 3 -(6-fluoro- 1, 1 -dimethyl-4- \ _ / \ _ / ((4-( 1 -methyl-3 -( 1 -( 1 - methylaz etidin-3-yl)ethoxy)- 1309 5-oxo- 1, 5-dihydro-4H-1,2,4- triazol-4-yl)phenyl)ethynyl)- 3-oxoisoindolin-2-yl)-2V- methylbenzamide \HN^0 FA IX N — ( ^zA 2-(3 -( l / / -imidazol-2-x) - = - < Hz x>N^ / \ _ / \ _ / yl)phenyl)-5 -fluoro-3,3 - dimethyl-7-((4-(l-methyl-3- ( 1 -(1 -methylazeti din-3 - 1310yl)ethoxy)-5-oxo-l,5- dihydro-4H-l,2,4-triazol-4- yl)phenyl)ethynyl)isoindolin- 1-oneHN-J'0 FA IX N — ( AzAxH) - = - (z x) 3 -(6-fluoro- 1, 1 -dimethyl-4- N^ / \ _ / \ _ / ((4-( 1 -methyl-3 -( 1 -( 1 - methylazetidin-3-yl)ethoxy)- 1311 5-oxo- 1, 5 -di hydro-4 / / - 1,2,4- triazol-4-yl)phenyl)ethynyl)- 3 -oxoisoindolin-2- I / O yl)benzamide \NH2DB1 / 166057797.1Docket No. 133447-5010-WO0 FI N — <z x> - = - (z x> 2-(3 -( 1H-imidazol-2- N^ / \ _ / \ _ / yl)phenyl)-7-((4-(3- cy cl opropoxy- 1 -methyl - 5 - 1312 / \ ZZ— oxo- 1,5 -dihydro-4H-1,2,4- J k!. triazol-4-yl)phenyl)ethynyl)- 5-fluoro-3,3- dimethylisoindolin- 1 -one ^ rN>HN-^70 FA IX N— < AzAx> - = - ( Hz x> 2-(3 -( 177-imidazol-2- \ _ / \ _ / , yl)phenyl)-3 -ethyl-5 -fluoro-3 - methyl-7-((4-(l-methyl-3- 1313 (oxetan-3 -yloxy)-5 -oxo- 1,5- dihydro-4H-1,2,4-triazol-4- Q— 'yl)phenyl)ethynyl)isoindolin- 7 zOy 1-oneHN— -2-(3 -( 1H-imidazol-2- yl)phenyl)-7-((4-(3 - cyclopropoxy-l-methyl-5- 1314 oxo- 1, 5 -dihydro-4H-1,2,4- triazol-4-yl)phenyl)ethynyl)- 3-ethyl-5-fluoro-3- methylisoindolin-1 -one0 FA IX N— ( A\zA 2-(3 -( 1H-imidazol-2-x) - = - ( Hz x>_ / \ _ / , y l)phenyl)-3 -ethyl-5 -fluoro-3 - methyl-7-((4-( 1 -methyl-3 -(( 1 - methylazetidin-3-yl)oxy)-5- 1315oxo- 1,5 -dihydro-4H-1,2,4- N—J triazol-4- yl)phenyl)ethynyl)isoindolin-Z1-oneDB1 / 166057797.1Docket No. 133447-5010-WO2-(3-(177-imidazol-2- yl)phenyl)-3 -ethy 1-5 -fluoro-3 - methyl-7-((4-( 1 -methy 1-3 -(( 1 - methylpiperidin-4-yl)oxy)-5- 1316oxo- 1,5 -di hydro-477- 1,2,4- triazol-4- yl)phenyl)ethynyl)isoindolin- 1-oneO F2-(3-(177-imidazol-2- i N— (Zy — = — (zy y l)phenyl)-3 -ethy 1-5 -fluoro-3 - \ _ / \ _ / , methyl-7-((4-(l-methyl-3-((2-.. ■ ■methyl-2- 1317 azaspiro[3.3]heptan-6- yl)oxy)-5 -oxo- 1,5 -dihydro- 4H-1,2,4-triazol-4- yl)phenyl)ethynyl)isoindolin- 1-one^\ / CO / ZC-NH0 VX \ / / "z z / 1— F-N IX / N— (Zy — = — ( Hzy 2-(3 -( l / 7-imidazol-2- \ / \ / | — NH yl)phenyl)-3-(azetidin-3- ylmethyl)-5-fluoro-7-((4-(3- 1318 methoxy- 1 -methyl-5-oxo- 1,5- di hydro-477- 1,2,4-triazol-4- yl)phenyl)ethynyl)isoindolin- 1-one ^ HYN-N#)0 Fi N— (Zy — = — (zy 2-(3 -( l / 7-imidazol-2- \ _ / \ _ / yl)phenyl)-3-cyclopropyl-5- fluoro-7-((4-(3 -methoxy- 1 - 1319 / ° methyl-5-oxo-l,5-dihydro- 4H-1,2,4-triazol-4- yl)phenyl)ethynyl)isoindolin- 1-oneuvDB1 / 166057797.1Docket No. 133447-5010-WO 0 FI N — <z x) - = - (z7\ _ / \ _ / , 2-(3 -( l / / -imidazol-2- yl)phenyl)-3 -ethyl-5 -fluoro-7- ((4-(3 -methoxy- 1 -methyl -5- 1320oxo- 1,5 -di hydro-477- 1,2,4- triazol-4-yl)phenyl)ethynyl)- 3 -methylisoindolin- 1 -one HN^0 F / / \ _ / / 'C N 2-(2-(3 -( 177-imidazol-2- — O H■ ■ ■ yl)phenyl)-6-fluoro-4-((4-(3 - o methoxy- 1 -m ethyl-5 -oxo- 1,5- 1321 / ° dihydro-4H-l,2,4-triazol-4- yl)phenyl)ethynyl)- 1 -methyl- 3-oxoisoindolin-l- 6^ yl)acetonitrile HN— -z^^A^S OC 0I FXZ zN—X AA / ~X <4I N— (z> - = - (z x> \ \ 2-(3 -( 1H-imidazol-2- \ _ / \ _ / yl)phenyl)-5-fluoro-7-((4-(3- methoxy- 1 -m ethyl-5 -oxo- 1,5- 1322 / ° dihydro-4H-1,2,4-triazol-4- yl)phenyl)ethynyl)-3-methyl- 3-(oxetan-3- ylmethyl)isoindolin- 1 -one HN~Az2-(3 -( 1H-imidazol-2- y 1 )pheny 1 )-5 -fluoro-7 -((4-(3- methoxy- 1 -methyl-5-oxo-l,5- 1323 dihydro-4H-1,2,4-triazol-4- yl)phenyl)ethynyl)-3-(2- methoxyethyl)-3- methylisoindolin- 1 -oneDB1 / 166057797.1Docket No. 133447-5010-WO0 Ff / \ _ f / C QHI N— <Z X) — = — <Z X) \ / 3 -(6-fluoro- 1 -(2-hy droxy-2- Ny / \ _ / \ _ / y— - methylpropyl)-4-((4-(3 - methoxy- 1 -methyl-5-oxo- 1,5- 1324 / < AV dihydro-4H-1,2,4-triazol-4- yl)phenyl)ethynyl)-l-methyl- 3-oxoisoindolin-2-yl)benzamide0 FN^\ f / \ / / C QH| N— (z x) = (z x) \ / 3 -(6-fluoro- 1 -(2-hy droxy-2-Ny / \ _ / \ — / y— methylpropyl)-4-((4-(3- methoxy- 1 -methyl-5-oxo-l,5- 1325 / °oSS>r \ dihydro-4H-1,2,4-triazol-4- yl)phenyl)ethynyl)-l-methyl- 3-oxoisoindolin-2-yl)-2V- dXy m ethy lb enzami de HN^O FN^\ f / _ / / C QH| N^Z x) - = - (z x> \ / \ _ / \ _ / y 77-(l-cyclopropyl-l / 7- pyrazol-3 -y 1 )- 3 -(6-fluoro- 1 - / ° (2-hydroxy-2-methylpropyl)- 4-((4-(3 -methoxy- 1 -methyl-5- 1326oxo- 1,5 -di hydro-477- 1,2,4- triazol-4-yl)phenyl)ethynyl)- 1-methyl-3-oxoisoindolin-2- N^ / NHyl)benzamide £> — NZJ0 FFA H 2-(3 -( 1H-imidazol-2- | N— (z x) <z x>Ny / \ / \ / yl)phenyl)-5-fluoro-3,3- dimethyl-7-((4-(l-methyl-3- ((l-methylazetidin-3- 1327 z° < Aky l)methoxy)-5-oxo- 1,5- dihydro-4H-1,2,4-triazol-4- yl)phenyl)ethynyl)isoindolin-N\ 1-oneHN— #DB1 / 166057797.1Docket No. 133447-5010-WO0 Fi N — <Z7 — = — (z7 3 -(6-fluoro- 1, 1 -dimethyl -4- \ _ / \ _ / ((4-( 1 -methyl-3 -(( 1 - methylazetidin-3- 1328 z° yl)methoxy)-5-oxo-l,5- dihydro-4H-1,2,4-triazol-4- yl)phenyl)ethynyl)-3- I J.,0 oxoisoindolin-2-yl)benzamide \NH2O F2-(3-(l / / -imidazol-2- i N — <Z7 — = — (z7\ _ / \ _ / yl)phenyl)-5-fluoro-3,3- dimethyl-7-((4-(l -methyl-3- (l-(oxetan-3-yl)ethoxy)-5- 1329oxo- 1,5-dihydro-4H-1,2,4- triazol-4- yl)phenyl)ethynyl)isoindolin- 1-oneHN-X^0 FAX AA rXi N— (Z3 -(6-fluoro- 1, 1 -dimethyl-4- 7 — = — (z7N^ / \ _ / \ _ / ((4-(l-methyl-3-((2-methyl-2- azaspiro[3.3]heptan-6- yl)oxy)-5-oxo-l,5-dihydro- 1330477-l,2,4-triazol-4- yl)phenyl)ethynyl)-3- oxoisoindolin-2-yl)-iV- methylbenzamide HN^0 F2-(3-(177-imidazol-2- A IX N— ( AZA H7 — = — (z7 yl)phenyl)-5-fluoro-3,3- N<=^ \ _ / \ _ / dimethyl-7-((4-(l -methyl-3- ((2-methyl-2- 1331 azaspiro[3.3]heptan-6- yl)oxy)-5 -oxo- 1,5 -dihydro- 4H-1,2,4-triazol-4- CXyN yl)phenyl)ethynyl)isoindolin- 1-oneHN--ZDB1 / 166057797.1Docket No. 133447-5010-WO0 FNX Hi N — (Z X) — = — <Z X) 3 -(6-fluoro- 1, 1 -dimethyl -4- \ _ / \ _ / ((4-(l-methyl-3-((2-methyl-2- azaspiro[3.3]heptan-6- 1332 X A yl)oxy)-5 -oxo- 1,5 -dihydro-4H-1,2,4-triazol-4- yl)phenyl)ethynyl)-3- oxoisoindolin-2-yl)benzamide NH20 FNX H 2-(3-(l / / -imidazol-2- I N— (z x) - = - <z x>N^ / \ _ / \ _ / yl)phenyl)-5-fluoro-3,3- dimethyl-7-((4-(l -methyl-5- oxo-3 -((2-oxopyrroli din-3 - 1333 °w / °y l)oxy)- 1, 5 -dihydro-4H- HN 3 / -V l,2,4-triazol-4- yl)phenyl)ethynyl)isoindolin- Ov1-one1334 enantiomer 1 of compound 1333 * —1335 enantiomer 2 of compound 1333 * —O F I N— (z x) - = - <z x>\ _ / \ _ / 3 -(6-fluoro- 1, 1 -dimethyl -4- ((4-(l-methyl-5-oxo-3-((2- oxopyrrolidin-3 -yl)oxy)- 1,5- 1336 °w y — / / ° ° N \ dihydro-4H-1,2,4-triazol-4- HN 5 / k yl)phenyl)ethynyl)-3 - oxoisoindolin-2-yl)benzamide CYoNH21337 enantiomer 1 of compound 1336 * —1338 enantiomer 2 of compound 1336 * —DB1 / 166057797.1Docket No. 133447-5010-WO0 F| N— (z x> - = - (z x> 3 -(6-fluoro- 1, 1 -dimethyl-4- N^ / \ _ / \ _ / ((4-(l-methyl-5-oxo-3-((2- oxopyrrolidin-3 -yl)oxy)- 1,5- 1339 °w / / °uN \ dihydro-4H-1,2,4-triazol-4-hn3 / L yl)phenyl)ethy nyl)-3 - oxoisoindolin-2-yl)-7V- Q yo methylbenzamide HN^1340 enantiomer 1 of compound 1339 * —1341 enantiomer 2 of compound 1339 * —I I o 2-(3-(l / / -imidazol-2- yl)phenyl)-7-((4-(3-((l,3- dimethylazeti din-3 -yl)oxy)- 1 - methyl-5-oxo-l,5-dihydro- 1342477-1,2,4-triazol-4- yl)phenyl)ethynyl)-3-ethyl-5- fluoro-3 -methyli soindolin- 1 - one^x'°'Z7z-O FNX AA H 2-(3 -( l / 7-imidazol-2- | N— (z x) - = - <z x) yl)phenyl)-5-fluoro-3,3- N=sy \ _ / \ _ / dimethyl-7-((4-(l-methyl-3- ((l-methyl-2-oxopyrrolidin-3- 1343 °W z°yl)oxy)-5-oxo-l,5-dihydro- ^-N 5 / L 4H-1,2,4-triazol-4- yl)phenyl)ethynyl)isoindolin- C^N1-oneHN-^0 FI N — <z x) - = - <z x> 3 -(6-fluoro- 1, 1 -dimethyl-4- N^ \ _ / \ _ / ((4-(l-methyl-3-((l-methyl-2- oxopyrrolidin-3-yl)oxy)-5- 1344 °X\ 7° oxo- 1,5 -dihydro-4H-1,2,4- ^N 3 / Us triazol-4-yl)phenyl)ethynyl)- 3 -oxoi soindolin-2- CL° yl)benzamideNH2DB1 / 166057797.1Docket No. 133447-5010-WO0 F| N— <z x> - = - <z x> 3 -(6-fluoro- 1, 1 -dimethyl-4- Ns- / \ _ / \ _ / ((4-( 1 -methyl-3-(( 1 -methyl-2- oxopyrrolidin-3-yl)oxy)-5- 1345 °W N - / / ° (UA NA N oxo- 1,5 -di hydro-47 / - 1,2,4- ^N 3 U- triazol-4-yl)phenyl)ethynyl)- 3-oxoisoindolin-2-yl)- / V- Gy methylbenzamide HN^1346 enantiomer 1 of compound 1345 * —1347 enantiomer 2 of compound 1345 * —0 FHNX ^A HI N — (z x) - = - (z x)Ns^ \ _ / \ _ / 3-(6-fluoro-4-((4-(3-methoxy- 5-oxo- 1, 5 -di hydro-47 / - 1,2,4- 1348 / ° triazol-4-yl)phenyl)ethynyl)- 1, 1 -dimethyl-3 -oxoisoindolin- 2-yl)- / V-methylbenzamideHN^Dj O FD^N IX N^Z x) - = - (z x>Ns- / \ _ / \ _ / 3-(6-fluoro-4-((4-(3-methoxy- 1-(methyl-d3)-5-oxo-1,5- dihydro-4H-1,2,4-triazol-4- 1349 / ° OAA yl)phenyl)ethynyl)- 1,1- dimethyl-3-oxoisoindolin-2- yl)-7V-methylbenzamide XyoHN^A oF| N— (z x> - = - (z x)Ns- / \ _ / \ _ / 3-(4-((4-( 1 -cyclopropyl-3 - methoxy-5-oxo-l,5-dihydro- 477- 1,2,4-triazol-4- 1350 / ° O'AAV yl)phenyl)ethynyl)-6-fluoro- 1, 1 -dimethyl-3 -oxoisoindolin- 2-yl)- / V-methylbenzamide AboHN^DB1 / 166057797.1Docket No. 133447-5010-WO3 -(6-fluoro-4-((4-(3 -methoxy- l-(oxetan-3-yl)-5-oxo-l,5- dihydro-4H-1,2,4-triazol-4- yl)phenyl)ethynyl)- 1,1- dimethyl-3-oxoisoindolin-2- yl)-A-methylbenzamide* Enantiomers were resolved with chiral chromatography, but the stereochemistry was not confirmed.

[0173] In some embodiments, the compound of formula (IA), formula (IIA), formula (IVA), formula (VIA), formula (VIIIA), or formula 1001-1351, or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, is a signal transducer and activator of transcription (STAT) protein inhibitor.

[0174] In some embodiments, the compound of formula (IA), formula (IIA), formula (IVA), formula (VIA), and / or formula (VIIIA), or formula 1001-1351, or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, is a STAT6 protein inhibitor.

[0175] In some embodiments, the compound of formula (IA), formula (IIA), formula (IVA), formula (VIA), formula (VIIIA), or formula 1001-1351, or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, has a cellular activity of at least about 10 μM as measured by an in vitro cellular assay. In some embodiments, the compound of formula (IA), formula (IIA), formula (IVA), formula (VIA), formula (VIIIA), or formula 1001- 1351, or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, has a cellular activity of about 10 μM or less as measured by an in vitro cellular assay. In some embodiments, the in vitro cellular assay used to measure the cellular activity is a STAT6 reporter cell assay.

[0176] In some embodiments, the compound of formula (IA), formula (IIA), formula (IVA), formula (VIA), formula (VIIIA), or formula 1001-1351, or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, has an IC50 of about 10 μM or less. In some embodiments, the compound of formula (IA), formula (IIA), formula (IVA),DB1 / 166057797.1Docket No. 133447-5010-WOformula (VIA), formula (VIIIA), or formula 1001-1351, or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, inhibits a STAT protein with an IC₅₀ of about 10 µM or less. In some embodiments, the compound of formula (IA), formula (IIA), formula (IVA), formula (VIA), formula (VIIIA), or formula 1001-1351, or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, inhibits STAT6 protein with an IC₅₀ of about 10 µM or less. In some embodiments, the IC₅₀ is measured by an in vitro cellular assay. In some embodiments, the in vitro cellular assay used to measure the IC₅₀ is a STAT6 reporter cell assay.

[0177] In some embodiments, the compound of formula (IA), formula (IIA), formula (IVA), formula (VIA), formula (VIIIA), or formula 1001-1351, or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, has a Kd of about 1 µM or less. In some embodiments, the compound of formula (IA), formula (IIA), formula (IVA), formula (VIA), formula (VIIIA), or formula 1001-1351, or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, binds to a STAT protein with a Kd of about 1 µM or less. In some embodiments, the compound of formula (IA), formula (IIA), formula (IVA), formula (VIA), formula (VIIIA), or formula 1001-1351, or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, binds to STAT6 protein with a Kd of about 1 µM or less.General Synthetic Procedures

[0178] The compounds of the disclosure may be prepared using the techniques described below. Some of the schemes and examples may omit details of common reactions, including oxidations, reductions, and so on, separation techniques (extraction, evaporation, precipitation, chromatography, filtration, trituration, crystallization, and the like), and analytical procedures, which are known to persons of ordinary skill in the art of organic chemistry. The details of such reactions and techniques can be found in a number of treatises, including Richard Larock, Comprehensive Organic Transformations (1999), and the multi -volume series edited by Michael B. Smith and others, Compendium of Organic Synthetic Methods (1974 et seq.). Some of the reaction schemes may omit minor products resulting from chemical transformations (e.g., an alcohol from the hydrolysis of an ester, CO₂ from the decarboxylation of a diacid, etc.). InDB1 / 166057797.1Docket No. 133447-5010-WOaddition, in some instances, reaction intermediates may be used in subsequent steps without isolation or purification ( / .<?., in situ).

[0179] Starting materials and reagents may be obtained from commercial sources or may be synthesized in analogy to or according to methods that are known in the art. In the preparation of starting materials, existing functional groups which do not participate in the reaction should, if necessary, be protected. Protecting groups, their introduction and their removal are described herein.

[0180] In some of the reaction schemes and examples described herein, certain compounds can be prepared using protecting groups, which prevent undesirable chemical reaction at otherwise reactive sites. Protecting groups may also be used to enhance solubility or otherwise modify physical properties of a compound. For a discussion of protecting group strategies, a description of materials and methods for installing and removing protecting groups, and a compilation of useful protecting groups for common functional groups, including amines, carboxylic acids, alcohols, ketones, aldehydes, and so on, see T. W. Greene and P. G. Wuts, Protecting Groups in Organic Chemistry (1999) and P. Kocienski, Protective Groups (2000).

[0181] Generally, the chemical transformations described throughout the specification may be carried out using substantially stoichiometric amounts of reactants, though certain reactions may benefit from using an excess of one or more of the reactants. Additionally, many of the reactions disclosed throughout the specification may be carried out at about room temperature (RT) and ambient pressure, but depending on reaction kinetics, yields, and so on, some reactions may be run at elevated pressures or employ higher temperatures (e.g., reflux conditions) or lower temperatures (e.g., -78° C. to 0° C ). Any reference in the disclosure to a stoichiometric range, a temperature range, a pH range, etc., whether or not expressly using the word “range,” also includes the indicated endpoints.

[0182] Many of the chemical transformations may also employ one or more compatible solvents, which may influence the reaction rate and yield. Depending on the nature of the reactants, the one or more solvents may be polar protic solvents (including water), polar aprotic solvents, non-polar solvents, or some combination. Representative solvents include saturated aliphatic hydrocarbons (e.g., n-pentane, n-hexane, n-heptane, n-octane); aromatic hydrocarbons (e.g., benzene, toluene, xylenes); halogenated hydrocarbons (e.g., methylene chloride,DB1 / 166057797.1Docket No. 133447-5010-WOchloroform, carbon tetrachloride); aliphatic alcohols (e.g., methanol, ethanol, propan-1 -ol, propan-2-ol, butan-l-ol, 2-methyl-propan-l-ol, butan-2-ol, 2-methyl-propan-2-ol, pentan- l-ol, 3- methyl-butan-l-ol, hexan-l-ol, 2-m ethoxy-ethanol, 2-ethoxy-ethanol, 2-butoxy-ethanol, 2-(2- methoxy-ethoxy)-ethanol, 2-(2-ethoxy-ethoxy)-ethanol, 2-(2-butoxy-ethoxy)-ethanol); ethers (e.g., diethyl ether, di-isopropyl ether, dibutyl ether, 1,2-dimethoxy ethane, 1,2-di ethoxy-ethane, 1 -methoxy-2-(2-methoxy-ethoxy)-ethane, 1 -ethoxy-2-(2-ethoxy-ethoxy )-ethane, tetrahydrofuran, 1,4-dioxane); ketones (e.g., acetone, methyl ethyl ketone); esters (methyl acetate, ethyl acetate); nitrogen-containing solvents (e g., formamide, N, N-dimethylformamide, acetonitrile, N-methyl- pyrrolidone, pyridine, quinoline, nitrobenzene); sulfur-containing solvents (e.g., carbon disulfide, dimethyl sulfoxide, tetrahydro-thiophene- 1,1, -dioxide); and phosphorus-containing solvents (e.g., hexamethylphosphoric triamide).

[0183] General Procedures 1A and 2A show exemplary methods for preparing compounds of formula (IA), formula (IIA), formula (IVA), formula (VIA), and / or formula (VIIIA), wherein the substituents are as defined for formula (IA), except where further noted. The following general procedures outline a key transformation used in the synthesis of 7-ethynylindoline-l-ones and its derivatives (i.e., compounds of formula (IA), formula (IIA), formula (IVA), formula (VIA), formula (VIIIA), or formula 1001-1351) by reacting a 7-haloisoindolin-l-one with a terminal aryl alkyne (General Procedure 1 A) or a 7-ethynylisoindolin-l-one with an aryl halide (General Procedure 2A) via a carbon-carbon bond-forming Sonogashira cross-coupling reaction, following standard literature-reported conditions. While these general procedures provide exemplary foundational methodology, variations in reagents, stoichiometry, reaction time, and temperature may apply depending on the specific compound, with detailed conditions reported alongside each individual example, as would be understood by one of ordinary skill in the art.DB1 / 166057797.1Docket No. 133447-5010-WOGeneral Procedure 1A. Exemplary Sonogashira cross-coupling of a 7-haloisoindolin-l-one (Intermediate I) with a terminal aryl alkyne (Intermediate II) to afford 7-ethynylindoline-l-one derivatives.XPhos Pd G3, Et3N DMF, 80 °CIntermediate I Intermediate IIGeneral Procedure 2A. Exemplary Sonogashira cross-coupling of a 7-ethynylisoindolin-l-one (Intermediate I) with an aryl halide (Intermediate II) to afford 7-ethynylindoline-l-one derivatives.XPhos Pd G3, Et3N DMF, 80 °CIntermediate II

[0184] Intermediates I and II of General Procedures 1A and 2A are readily accessible using established literature protocols, and the commercially available building blocks and synthetic intermediates used in the preparation of compounds 1001-1351 are described in the “ Synthesis of Intermediates'’’ section of Example 1. In General Procedures 1A and 2A, “XPhos Pd G3” is 2- Dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'-biphenyl)[2-(2'-amino-l,r- biphenyl)]palladium(II) methanesulfonate; “EtsN” is triethylamine; “DMF” is dimethylformamide; and “X” represents a halide.Pharmaceutical Compositions

[0185] In one aspect, the disclosure provides a pharmaceutical composition comprising any of the compounds described herein, or a pharmaceutically acceptable salt, solvate, hydrate,DB1 / 166057797.1Docket No. 133447-5010-WOcocrystal, or prodrug thereof, and a physiologically compatible carrier medium. In one embodiment, the disclosure provides a pharmaceutical composition comprising: a compound of formula (IA), formula (IIA), formula (IVA), formula (VIA), formula (VIIIA), or formula 1001- 1351, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof; and a physiologically compatible carrier medium. In one embodiment, the disclosure provides a pharmaceutical composition comprising: a therapeutically effective amount of a compound described herein (e.g., a compound of formula (IA), formula (IIA), formula (IVA), formula (VIA), formula (VIIIA), or formula 1001-1351), or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof; and a physiologically compatible carrier medium.

[0186] In one embodiment, the disclosure provides a pharmaceutical composition comprising: a compound described herein (e.g., a compound of formula (IA), formula (IIA), formula (IVA), formula (VIA), formula (VIIIA), or formula 1001-1351), or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof; and a physiologically compatible carrier medium for use in the treatment of the diseases and conditions described herein. In one embodiment, the disclosure provides a pharmaceutical composition comprising: a therapeutically effective amount of a compound described herein (e.g., a compound of formula (IA), formula (IIA), formula (IVA), formula (VIA), formula (VIIIA), or formula 1001-1351), or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof; and a physiologically compatible carrier medium for use in the treatment of the diseases and conditions described herein.

[0187] Each compound described herein (e.g., a compound of formula (IA), formula (IIA), formula (IVA), formula (VIA), formula (VIIIA), or formula 1001-1351), or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, is effective over a wide dosage range. Accordingly, the amount or dose of the compound of formula (IA), formula (IIA), formula (IVA), formula (VIA), formula (VIIIA), or formula 1001-1351, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, provided in a pharmaceutical composition of the disclosure may range from 0.001 to 1000 mg. The exact amount or dose will depend upon the route of administration, the form in which the compound is administered, the gender and age of the subject to be treated, the bodyDB1 / 166057797.1Docket No. 133447-5010-WOweight of the subject to be treated, and the preference and experience of the attending physician. The clinically-established dosages of the compound of the disclosure, or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, may also be used if appropriate.Methods of Treatment

[0188] The compounds and pharmaceutical compositions described herein can be used in methods for treating diseases and / or disorders. In some embodiments, the compounds and pharmaceutical compositions described herein can be used in methods for treating an allergic disease, an inflammatory disease, or an autoimmune disease. In some embodiments, the compounds and pharmaceutical compositions described herein can be used in methods for treating a disease or disorder alleviated by inhibiting signal transducer and activator of transcription (STAT) protein activity. In some embodiments, the compounds and pharmaceutical compositions described herein can be used in methods for treating a disease or disorder alleviated by inhibiting STAT6 protein activity.

[0189] In one aspect, the disclosure provides a method of treating a disease or disorder in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (IA), formula (IIA), formula (IVA), formula (VIA), formula (VIIIA), or formula 1001-1351, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof. In another aspect, the disclosure provides a method of treating a disease or disorder in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising: (i) a compound of formula (IA), formula (IIA), formula (IVA), formula (VIA), formula (VIIIA), or formula 1001-1351, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof; and (ii) a physiologically compatible carrier medium.

[0190] In some embodiments, the method of treating a disease or disorder in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a compound described herein (e.g., a compound of formula (IA), formula (IIA), formula (IVA), formula (VIA), formula (VIIIA), or formula 1001-1351), or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein the disease or disorder is DB1 / 166057797.1Docket No. 133447-5010-WOalleviated by inhibiting STAT protein activity in the patient. In some embodiments, the method of treating a disease or disorder in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a compound described herein (e.g., a compound of formula (IA), formula (IIA), formula (IVA), formula (VIA), formula (VIIIA), or formula 1001- 1351), or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein the disease or disorder is alleviated by inhibiting STAT6 protein activity in the patient.

[0191] In some embodiments, the method of treating a disease or disorder in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound described herein (e.g., a compound of formula (IA), formula (IIA), formula (IVA), formula (VIA), formula (VIIIA), or formula 1001- 1351), or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof; and a physiologically compatible carrier medium, wherein the disease or disorder is alleviated by inhibiting STAT protein activity in the patient. In some embodiments, the method of treating a disease or disorder in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound described herein (e.g., a compound of formula (IA), formula (IIA), formula (IVA), formula (VIA), formula (VIIIA), or formula 1001-1351), or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof; and a physiologically compatible carrier medium, wherein the disease or disorder is alleviated by inhibiting STAT6 protein activity in the patient.

[0192] In some embodiments, the method of treating a disease or disorder in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a compound (e.g., a compound of formula (IA), formula (IIA), formula (IVA), formula (VIA), formula (VIIIA), or formula 1001-1351), or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, or a therapeutically effective amount of a pharmaceutical composition, as described herein, wherein the disease or disorder is selected from an allergic disease, an inflammatory disease, and an autoimmune disease. In some embodiments, the method of treating a disease or disorder in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a compound (e.g, a compound of formula (IA),DB1 / 166057797.1Docket No. 133447-5010-WOformula (IIA), formula (IVA), formula (VIA), formula (VIIIA), or formula 1001-1351), or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, or a therapeutically effective amount of a pharmaceutical composition, as described herein, wherein the disease or disorder is an allergic disease and / or an inflammatory disease. In some embodiments, the method of treating a disease or disorder in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a compound (e.g, a compound of formula (IA), formula (IIA), formula (IVA), formula (VIA), formula (VIIIA), or formula 1001-1351), or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, or a therapeutically effective amount of a pharmaceutical composition, as described herein, wherein the disease or disorder is an allergic disease. In some embodiments, the method of treating a disease or disorder in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a compound (e.g, a compound of formula (IA), formula (IIA), formula (IVA), formula (VIA), formula (VIIIA), or formula 1001-1351), or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, or a therapeutically effective amount of a pharmaceutical composition, as described herein, wherein the disease or disorder is an inflammatory disease. In some embodiments, the method of treating a disease or disorder in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a compound (e.g., a compound of formula (IA), formula (IIA), formula (IVA), formula (VIA), formula (VIIIA), or formula 1001-1351), or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, or a therapeutically effective amount of a pharmaceutical composition, as described herein, wherein the disease or disorder is an autoimmune disease.

[0193] In some embodiments, the method of treating a disease or disorder in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a compound (e.g, a compound of formula (IA), formula (IIA), formula (IVA), formula (VIA), formula (VIIIA), or formula 1001-1351), or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, or a therapeutically effective amount of a pharmaceutical composition, as described herein, wherein the disease or disorder is associated with activation of Th2 cells, selected from an allergic disease, an inflammatory disease, and an autoimmune disease.DB1 / 166057797.1Docket No. 133447-5010-WO

[0194] In some embodiments, the method of treating a disease or disorder in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a compound described herein (e.g., a compound of formula (IA), formula (IIA), formula (IVA), formula (VIA), formula (VIIIA), or formula 1001-1351), or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein the disease or disorder is alleviated by inhibiting activation of Th2 cells in the patient. In some embodiments, the method of treating a disease or disorder in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a compound described herein (e.g., a compound of formula (IA), formula (IIA), formula (IVA), formula (VIA), formula (VIIIA), or formula 1001- 1351), or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein the disease or disorder is alleviated by inhibiting activation of Th2 cells in the patient.

[0195] In some embodiments, the method of treating a disease or disorder in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a compound (e.g, a compound of formula (IA), formula (IIA), formula (IVA), formula (VIA), formula (VIIIA), or formula 1001-1351), or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, or a therapeutically effective amount of a pharmaceutical composition, as described herein, wherein the disease or disorder is an allergic disease or condition associated with activation of Th2 cells.

[0196] In some embodiments, the allergic disease or condition is selected from asthma, eosinophilic esophagitis (EoE), allergic contact dermatitis, alopecia areata, allergic bronchopulmonary aspergillosis, allergic rhinitis, Netherton syndrome, and chronic eosinophilic pneumonia.

[0197] In some embodiments, the method of treating a disease or disorder in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a compound (e.g, a compound of formula (IA), formula (IIA), formula (IVA), formula (VIA), formula (VIIIA), or formula 1001-1351), or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, or a therapeutically effective amount of a pharmaceutical composition, as described herein, wherein the disease or disorder is an inflammatory disease or condition associated with activation of Th2 cells.DB1 / 166057797.1Docket No. 133447-5010-WO

[0198] In some embodiments, the inflammatory disease or condition is selected from atopic dermatitis, chronic rhinosinusitis with nasal polyposis (CRSwNP), prurigo nodularis (PN), chronic spontaneous urticaria, bullous pemphigoid, and nummular eczema.

[0199] In some embodiments, the method of treating a disease or disorder in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a compound described herein (e.g, a compound of formula (IA), formula (IIA), formula (IVA), formula (VIA), formula (VIIIA), or formula 1001-1351), or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein the disease or disorder is alleviated by inhibiting STAT protein activity in the patient. In some embodiments, the method of treating a disease or disorder in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a compound described herein (e.g., a compound of formula (IA), formula (IIA), formula (IVA), formula (VIA), formula (VIIIA), or formula 1001- 1351), or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein the disease or disorder is alleviated by inhibiting STAT6 protein activity in the patient.

[0200] In some embodiments, the method of treating a disease or disorder in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound described herein (e.g, a compound of formula (IA), formula (IIA), formula (IVA), formula (VIA), formula (VIIIA), or formula 1001- 1351), or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof; and a physiologically compatible carrier medium, wherein the disease or disorder is alleviated by inhibiting STAT protein activity in the patient. In some embodiments, the method of treating a disease or disorder in a patient in need thereof comprises administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound described herein (e.g, a compound of formula (IA), formula (IIA), formula (IVA), formula (VIA), formula (VIIIA), or formula 1001-1351), or pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof; and a physiologically compatible carrier medium, wherein the disease or disorder is alleviated by inhibiting STAT6 protein activity in the patient.DB1 / 166057797.1Docket No. 133447-5010-WO

[0201] In some embodiments, the patient or subject is a mammal. In an embodiment, the patient or subject is a human. In an embodiment, the patient or subject is a companion animal. In an embodiment, the patient or subject is a canine, feline, or equine.

[0202] In some embodiments, the compound of formula (IA), formula (IIA), formula (IVA), formula (VIA), formula (VIIIA), or formula 1001-1351, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof is administered in a unit dosage form.Dosages and Dosing Regimens

[0203] The amounts of the compounds or pharmaceutical compositions administered using the methods described herein, such as the compounds of formula (IA), formula (IIA), formula (IVA), formula (VIA), formula (VIIIA), or formula 1001-1351, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, will be dependent on the human or mammal being treated, the severity of the disease or disorder, the rate of administration, the disposition of the active pharmaceutical ingredients, and the discretion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 600 mg per kg body weight per day.

[0204] An effective amount of the active pharmaceutical ingredients of formula (IA), formula (IIA), formula (IVA), formula (VIA), formula (VIIIA), or formula 1001-1351, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, or pharmaceutical compositions thereof, may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0205] In embodiments, the compositions described herein further include controlled-release, sustained release, or extended-release therapeutic dosage forms for administration of the compounds described herein, which involves incorporation of the compounds into a suitable delivery system in the formation of certain compositions. This dosage form controls release of the compound(s) in such a manner that an effective concentration of the compound(s) in theDB1 / 166057797.1Docket No. 133447-5010-WObloodstream may be maintained over an extended period of time, with the concentration in the blood remaining relatively constant, to improve therapeutic results and / or minimize side effects. Additionally, a controlled-release system would provide minimum peak to trough fluctuations in blood plasma levels of the compound.EXAMPLES

[0206] The embodiments encompassed herein are now described with reference to the following examples. These examples are provided for the purpose of illustration only and the disclosure encompassed herein should in no way be construed as being limited to these examples, but rather should be construed to encompass any and all variations which become evident as a result of the teachings provided herein. It should be appreciated by those of skill in the art that the techniques disclosed in the following examples represent approaches that have been found to function well in the practice of the disclosure. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments that are described herein and still obtain a like or similar result without departing from the spirit and scope of the disclosure.List of Abbreviations

[0207] In the accompanying procedures and schemes, abbreviations are used with the following meanings unless otherwise indicated: ACN = acetonitrile; AIBN = 2-(1-cyano-1-methylethylazo)-2-methylpropiononitrile; Boc = tertbutyloxy carbonyl; BPO = Benzoyl peroxide; CDI = di(l / / -imidazol-l-yl)methanone; Cu(OAc)2 = Copper(II) acetate; DCE = 1,2- dichloroethane; DIPEA = A-ethyl-A-isopropylpropan-2-amine; DMF = dimethylformamide; DMSO = (methyl sulfmyl)methane; DMA = dimethylacetamide; DME = 1,2-Dimethoxy ethane; DMEDA = / V'A^-dimethylethane- 1,2-diamine, DMP = Dess-Martin periodinane, 3-oxo-lk5- benzo[ ][l,2]iodaoxole-l,l,l(3 / / )-triyl triacetate; EDC1 = 3-(((ethylimino)methylene)amino)- 7V, A-dimethylpropan-l -amine; EtOAc = ethyl acetate; FA = formic acid; h = hour; HATU = 1- [Bis(dimethylamino)methylene]-1 / -l,2,3-triazolo[4,5-Z>]pyridinium 3-oxid hexafluorophosphate; HFIP = hexafluoro-2-propanol; HOBt = l / 7-benzo[<7][l,2,3]triazol-l-ol; IPA = isopropanol alcohol; Ir(dF(CF3)ppy)2(dtbpy)(PF6) = [4,4'-BA(l,l-dimethylethyl)-2,2'- bipyridine-N1,N1′]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]Iridium(III) hexafluorophosphate; MeOH = methanol; NBS = l-bromo-2,5-pyrrolidinedione; NCS = N- DB1 / 166057797.1Docket No. 133447-5010-WOchlorosuccinimide; NiCl2.dtbbpy = [4,4'-Bis(l,l-dimethylethyl)-2,2'-bipyridine] nickel (TI) dichloride; NIS = N-Iodosuccinimide; 1 -iodopyrrolidine-2, 5-dione; NMI = 1 -methylimidazole; Pd2(dba)3= Tris(dibenzylideneacetone)dipalladium(0); Pd(dppf)Cl2= [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pd(dppf)Cl2·CH2Cl2= [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane;Pd(OAc)2 = Palladium(II) acetate; PMBC1 = 4-methoxybenzoyl chloride; Pd(PPh3)2Cl2= Bis(triphenylphosphine)palladium(II) dichloride; Pd(PPh3)2Cl2·CH2Cl2= Bis(triphenylphosphine)palladium(II) dichloride, complex with dichloromethane; PE = petroleum ether; PTSA = 4-methylbenzenesulfonic acid; SEM-C1 = (2- (chloromethoxy)ethyl)trimethylsilane; TCFH = A-(chloro(dimethylamino)methylene)-A- methylmethanaminium; TCM = trichloromethane; THF = tetrahydrofuran; TEA = triethylamine; TFA = trifluoroacetic acid; TfOH = trifluoromethanesulfonic acid; THP = tetrahydropyran; TTMSS = Tris(trimethylsilyl)silane; XantPhos = 4,5-Bis(diphenylphosphino)-9,9- dimethylxanthene; XPhos = 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; and XPhos Pd G3 = 2-Dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'-biphenyl)[2-(2'-amino-l,r- biphenyl)]palladium(II) methanesulfonate.Example 1: Preparation of 7-ethynylindoline-l-ones and derivatives thereof.

[0208] The following example describes the preparation of compounds 1001-1351.Compound names were generated using ChemDraw (version 23.1.1 and version 22.2.0). Tothe extent that there are discrepancies between the name of a compound and its depicted structure, the depicted chemical structure is to be taken as the appropriate compound. Any one of compounds 1001-1351 can be isolated in neutral form or salt form, depending on reaction and / or purification conditions.

[0209] The following general procedures outline a key transformation used in the synthesis of 7-ethynylindoline-l-ones and its derivatives described herein (Compounds 1001-1351) by reacting a 7-haloisoindolin-l-one with a terminal aryl alkyne (General Procedure 1A) or a 7- ethynylisoindolin-l-one with an aryl halide (General Procedure 2A) via a carbon-carbon bondforming Sonogashira cross-coupling reaction, following standard literature-reported conditions. While these general procedures provide exemplary foundational methodology, variations in reagents, stoichiometry, reaction time, and temperature may apply depending on the specificDB1 / 166057797.1Docket No. 133447-5010-WOcompound, with detailed conditions reported alongside each individual example, as would be understood by one of ordinary skill in the art.General Procedure 1A. Exemplary Sonogashira cross-coupling of a 7-haloisoindolin-l-one (Intermediate I) with a terminal aryl alkyne (Intermediate II) to afford 7-ethynylindoline-l-one derivatives.XPhos Pd G3, Et3N DMF, 80 °CIntermediate IIGeneral Procedure 2A. Exemplary Sonogashira cross-coupling of a 7-ethynylisoindolin-l-one (Intermediate I) with an aryl halide (Intermediate II) to afford 7-ethynylindoline-l-one derivatives.XPhos Pd G3, Et3N DMF, 80 °CIntermediate II

[0210] Intermediates I and II of General Procedures 1A and 2A are readily accessible using established literature protocols, and the commercially available building blocks and synthetic intermediates used in the preparation of compounds 1001-1351 are described in the “ Synthesis of Intermediates’' section of Example 1. In General Procedures 1A and 2A, “EtsN” is triethylamine; and “X” represents a halide.DB1 / 166057797.1Docket No. 133447-5010-WOSynthesis of Intermediates Used in the Preparation of Compounds 1001-1351A. Intermediate I

[0211] Synthesis of methyl 3-(7-bromo-l-oxoisoindolin-2-yl)benzoate (Intermediate 1.1)

[0212] Step 1: Synthesis of methyl 3-(7-bromo-l-oxoisoindolin-2-yl)benzoate

[0213] To a solution of 7-bromoisoindolin-l-one (8.00 g, 37.7 mmol) and methyl 3- iodobenzoate (9.89 g, 37.7 mmol) in DMSO (88.9 mL) were added Cui (479 mg, 7.55 mmol) and N, N' -dimethylethylenediamine (DMEDA; 665 mg, 7.55 mmol) in one portion. The reaction mixture was stirred at 100 °C for 3 h, then diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 * 200 mL), dried over Na₂SO₄, filtered, and concentrated. The crude residue was purified by column chromatography (Stationary phase: Silica gel; Mobile phase: A = petroleum ether, B = EtOAc; Gradient: 10-100% B) to afford the title compound. LC-MS (ESI+): m / z = 348.0 [M+H]+.

[0214] Synthesis of methyl 3-(7-bromo-l-oxoisoindolin-2-yl)-2-fluorobenzoate (Intermediate 1.2)

[0215] Step 1: Synthesis of methyl 2-bromo-6-(bromomethyl)benzoate

[0216] To a solution of benzoyl peroxide (BPO; 7.4 g, 30.6 mmol) in carbon tetrachloride (CCL; 1.0 L) were added A-bromosuccinimide (NBS; 54.4 g, 306 mmol) and methyl 2-bromo-6- methylbenzoate (70.0 g, 306 mmol) in one portion. The reaction mixture was stirred at 80 °C for 12 h, then diluted with water (1.0 L) and extracted with EtOAc (3 x 800 mL). The combined organic layers were washed with brine (2 * 1.0 L), dried over Na₂SO₄, filtered, and concentrated to afford the title compound. ’H NMR (400 MHz, DMSO-ds): 5 = 7.70 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.47-7.41 (m, 1H), 4.67-4.63 (m, 2H), 3.92 (s, 3H).DB1 / 166057797.1Docket No. 133447-5010-WO

[0217] Step 2: Synthesis of methyl 3-((3-bromo-2-(methoxycarbonyl)benzyl)amino)-2- fluorobenzoate

[0218] A mixture of methyl 2-bromo-6-(bromomethyl)benzoate (2.00 g, 6.49 mmol), methyl 3-amino-2-fluorobenzoate (1.15 g, 6.82 mmol), and DIPEA (3.39 mL, 19.5 mmol) in acetonitrile (15 mL) was stirred at 80 °C for 16 h. The reaction mixture was concentrated in vacuo to afford a residue, which was purified by flash chromatography (Instrument: Biotage Isolera Prime;Column: 120 g SepaFlash® Silica Flash Column; Mobile phase: A = hexane, B = EtOAc;Gradient: 0-10% B over 150 min; Flow rate: 100 mL / min) to afford the title compound. LC-MS (ESI+): m / z = 397.6 [M+H]’.

[0219] Step 3: Synthesis of methyl 3-(7-bromo-l-oxoisoindolin-2-yl)-2-fluorobenzoate

[0220] To a solution of methyl 3-((3-bromo-2-(methoxycarbonyl)benzyl)amino)-2- fluorobenzoate (1.20 g, 3.03 mmol) in methanol (10 mL) was added tri ethylamine (TEA; 1.26 mL, 9.09 mmol). The reaction mixture was stirred at 40 °C for 16 h, then filtered to yield the title compound. LC-MS (ESI+): m / z = 363.9 [M+H],

[0221] Synthesis of methyl 5-(7-bromo-l-oxo-5-(trifluoromethyl)isoindolin-2-yl)-2- fluorobenzoate (Intermediate 1.3)A. / rvV / v*

[0222] Step 1: Synthesis of methyl 2-bromo-6-fluoro-4-(trifluoromethyl)benzoate

[0223] To a solution of 2-bromo-6-fluoro-4-(trifluoromethyl)benzoic acid (2.50 g, 8.71 mmol) inDMF (25 mL) were added potassium carbonate (K2CO3; 1.81 g, 13.1 mmol) and iodomethane (1.85 g, 13.1 mmol). The reaction mixture was stirred at 20 °C for 2 h, then diluted with water (50 mL) and extracted with EtOAc (3 * 50 mL). The combined organic layers were washed with saturated NaCl (50 mL), dried over Na₂SO₄, filtered, and concentrated underDB1 / 166057797.1Docket No. 133447-5010-WOreduced pressure to afford the title compound. ’H NMR (400 MHz, CDCL): 8 = 7.70 (s, 1H), 7.40 (d, J = 8.5 Hz, 1H), 4.02 (s, 3H).

[0224] Step 2: Synthesis of methyl 2-bromo-6-(nitromethyl)-4-(trifluoromethyl)benzoate

[0225] To a solution of nitromethane (203 mg, 3.32 mmol) in DMSO (10 mL) was added potassium tert-butoxide (337 mg, 3.32 mmol). The mixture was stirred at 20 °C for 30 min under a nitrogen atmosphere. Methyl 2-bromo-6-fluoro-4-(trifluoromethyl)benzoate (500 mg, 1.66 mmol) was then added, and the reaction was stirred at 20 °C for 12 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (Instrument: Biotage Isolera Prime; Column: 12 g SepaFlash® Silica Flash Column; Mobile phase: A = petroleum ether, B = EtOAc; Gradient: 0- 10% B over 10 min; Flow rate: 60 mL / min) to afford the title compound.1H NMR (400 MHz, CDCL): 8 = 8.01 (s, 1H), 7.72 (s, 1H), 5.58 (s, 2H), 4.03 (s, 3H).

[0226] Step 3: Synthesis of 7-bromo-5-(trifluoromethyl)isoindolin-l-one

[0227] To a solution of methyl 2-bromo-6-(nitromethyl)-4-(trifluoromethyl)benzoate (1.70 g, 4.97 mmol) in ethanol (20 mL) and water (3 mL) were added iron powder (2.25 g, 40.3 mmol) and ammonium chloride (2.16 g, 40.3 mmol). The reaction mixture was stirred at 65 °C for 4 h, then filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Instrument: Biotage Isolera Prime; Column: 20 g SepaFlash® Silica Flash Column; Mobile phase: A = petroleum ether, B = EtOAc; Gradient: 0-60% B over 10 min; Flow rate: 30 mL / min) to afford the title compound. LC-MS (ESI+): m / z = 280.0 [M+H]+.

[0228] Step 4: Synthesis of methyl 5-(7-bromo-l-oxo-5-(trifluoromethyl)isoindolin-2-yl)-2- fluorobenzoate

[0229] A mixture of 7-bromo-5-(trifluoromethyl)isoindolin-l-one (700 mg, 2.50 mmol), methyl 2-fluoro-5-iodobenzoate (700 mg, 2.50 mmol), Cui (95.2 mg, 0.50 mmol), N, N'- dimethylethylenediamine (DMEDA; 44.1 mg, 0.50 mmol), and K2CO3 (1.04 g, 7.50 mmol) in toluene (10 mL) was degassed and purged with nitrogen three times. The mixture was stirred at 70 °C for 1 h under nitrogen. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography (Instrument: Biotage Isolera Prime; Column: 20 gDB1 / 166057797.1Docket No. 133447-5010-WOSepaFlash® Silica Flash Column; Mobile phase: A = petroleum ether, B = EtOAc; Gradient: 0- 10% B over 10 min; Flow rate: 60 mL / min) to afford the title compound. LC-MS (ESI+): m / z = 432.1 [M+H]+.

[0230] Synthesis of methyl 5-(7-bromo-l-oxoisoindolin-2-yl)-2-fluorobenzoate (Intermediate 1.4)

[0231] Step 1: Synthesis of methyl 5-(7-bromo-l-oxoisoindolin-2-yl)-2-fluorobenzoate

[0232] To a solution of methyl 5-amino-2-fluorobenzoate (1.60 g, 9.46 mmol) and methyl 2- bromo-6-(bromomethyl)benzoate (3.00 g, 9.74 mmol, from Intermediate 1.2) in acetonitrile (30 mb) was added potassium carbonate (K2CO3; 4.04 g, 29.2 mmol) at 20 °C. The reaction mixture was stirred at 80 °C for 16 h, then diluted with water (50 mb) and extracted with EtOAc (3 * 30 mb). The combined organic layers were washed with brine (2 x 40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford a residue. The residue was purified by flash chromatography (Instrument: Biotage Isolera Prime; Column: 20 g SepaFlash® Silica Flash Column; Mobile phase: A = hexane, B = EtOAc; Gradient: 0-50% B over 20 min; Flow rate: 70 mL / min) to afford the title compound. LC-MS (ESI+): m / z = 365.8 [M+H]++.

[0233] Synthesis of methyl 3-(4-chloro-5-oxo-5,7-dihydro-6Z7-pyrrolo[3,4-b]pyridin-6-yl)-2- fluorobenzoate (Intermediate 1.5)

[0234] Step 1: Synthesis of methyl 2-(bromomethyl)-4-chloronicotinate

[0235] To a solution of methyl 4-chloro-2-methylnicotinate (6.00 g, 32.3 mmol) in carbon tetrachloride (CCL; 120 mL) were added / V-bromosuccinimide (NBS; 7.48 g, 42.0 mmol) and azobisisobutyronitrile (AIBN; 531 mg, 3.23 mmol) at 20 °C under a nitrogen atmosphere. The mixture was stirred at 90 °C for 12 h under nitrogen. The reaction was quenched with water (60 mL) and extracted with DCM (3 x 60 mL). The combined organic layers were washed with brineDB1 / 166057797.1Docket No. 133447-5010-WO(60 mL), dried over Na2SO4, filtered, and concentrated to afford a residue. The residue was purified by flash chromatography (Instrument: Biotage Isolera Prime; Column: 80 g SepaFlash® Silica Flash Column; Mobile phase: A = hexane, B = EtOAc; Gradient: 0-5% B over 5 min; Flow rate: 100 mL / min) to afford the title compound. LC-MS (ESI+): m / z = 263.9 [M+H]+.1H NMR (400 MHz, MeOD-d4): 5 = 8.53 (d, J = 5.6 Hz, 1H), 7.55 (d, J = 5.6 Hz, 1H), 4.63 (s, 2H), 4.00 (s, 3H).

[0236] Step 2: Synthesis of methyl 4-chloro-2-(((2-fluoro-3- (methoxycarbonyl)phenyl)amino)methyl)nicotinate

[0237] To a solution of methyl 2-(bromomethyl)-4-chloronicotinate (1.00 g, 3.78 mmol) and methyl 3 -amino-2 -fluorobenzoate (512 mg, 3.02 mmol) in acetonitrile (20 mL) was added N, N- diisopropylethylamine (DIPEA; 977 mg, 7.56 mmol) at 20 °C. The mixture was stirred at 80 °C for 12 h, then concentrated under reduced pressure. The residue was purified by flash chromatography (Instrument: Biotage Isolera Prime; Column: 12 g SepaFlash® Silica Flash Column; Mobile phase: A = hexane, B = EtOAc; Gradient: 0-30% B over 5 min; Flow rate: 80 mL / min) to afford the title compound. LC-MS (ESI+): m / z = 353.0 [M+H]+.

[0238] Step 3: Synthesis of methyl 3-(4-chloro-5-oxo-5,7-dihydro-6 / 7-pyrrolo[3,4-b]pyridin- 6-yl)-2 -fluorobenzoate

[0239] To a solution of methyl 4-chloro-2-(((2-fluoro-3- (methoxycarbonyl)phenyl)amino)methyl)nicotinate (650 mg, 1.84 mmol) in methanol (12 mL) was added triethylamine (TEA; 373 mg, 3.69 mmol) at 20 °C. The mixture was stirred at 40 °C for 12 h after which the precipitate was removed by filtration. The solid was dried under vacuum to afford the title compound. LC-MS (ESI+): m / z = 321.0 [M+H]+.

[0240] Synthesis of methyl 3-(7-bromo-l-oxo-5-(trifluoromethyl)isoindolin-2-yl)benzoate (Intermediate 1.6)

[0241] Step 1: Synthesis of methyl 3-(7-bromo-l-oxo-5-(trifluoromethyl)isoindolin-2- yl)benzoateDB1 / 166057797.1Docket No. 133447-5010-WO

[0242] A mixture of 7-bromo-5-(trifluoromethyl)isoindolin-l-one (100 mg, 357 pmol, from Intermediate 1.3), methyl 3 -iodobenzoate (154 mg, 589 pmol), potassium carbonate (K2CO3; 163 mg, 1.18 mmol), copper(I) iodide (Cui; 15 mg, 78.6 pmol), and N, N'- dimethylethylenediamine (DMEDA; 6.93 mg, 78.6 pmol) in toluene (2.0 mL) was degassed and purged with nitrogen three times. The reaction mixture was stirred at 90 °C for 1 h under a nitrogen atmosphere. It was then filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (Instrument: Biotage Isolera Prime; Column: 4 g SepaFlash® Silica Flash Column; Mobile phase: A = petroleum ether, B = EtOAc; Gradient: 0-30% B over 10 min; Flow rate: 30 mL / min) to afford the title compound. LC-MS (ESI+): m / z = 414.0 [M+H]~.

[0243] Synthesis of 2-fluoro-3-(7-iodo-l-oxo-5-(trifluoromethyl)isoindolin-2-yl)benzamide (Intermediate 1.7)9 i 9 9?. ", i... Ji,. A.. °?...

[0244] Step 1: Synthesis of 2-iodo-6-methyl-4-(trifluoromethyl)benzoic acid

[0245] A mixture of 2-methyl-4-(trifluoromethyl)benzoic acid (4 g, 19.6 mmol), iodobenzene diacetate (8.84 g, 27.4 mmol), I2(9.95 g, 39.2 mmol) and Pd(OAc)2 (444 mg, 1.96 mmol) in DMF (40 mb) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 12 h under N₂ atmosphere. After completion the pH of the mixture was adjusted to ~4 using 2 M HC1, diluted with water (100 mL) and extracted with DCM (2 x 100 mb). The combined organic extracts were added to 20 mL of 2M aqueous NaOH and extracted with water (2 x 100 mL). The combined aqueous phase was acidifed to pH ~4 with 2M HC1 and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Instrument: Biotage Isolera Prime; Column: 40 g SepaFlash®DB1 / 166057797.1Docket No. 133447-5010-WOSilica Flash Column; Mobile phase: A = petroleum ether, B = EtOAc; Gradient: 0-10% B over 15 min; Flow rate: 60 mL / min) to afford the title compound. LC-MS (ESI⁻): m / z = 328.9 [M– H]-.1H NMR (400 MHz, DMSO-ds): 8 = 14.27-13.03 (m, 1H), 8.00 (s, 1H), 7.70 (s, 1H), 2.38 (s, 3H).

[0246] Step 2: Synthesis of methyl 2-iodo-6-methyl-4-(trifluoromethyl)benzoate

[0247] To a solution of 2-iodo-6-methyl-4-(trifluoromethyl)benzoic acid (4.5 g, 13.6 mmol) in DMF (40 mL) was added K₂CO₃ (3.77 g, 27.3 mmol) and Mel (2.9 g, 20.5 mmol). The mixture was stirred at 20 °C for 12 h. The mixture was diluted with H₂O (100 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Instrument: Biotage Isolera Prime; Column: 40 g SepaFlash® Silica Flash Column; Mobile phase: A = petroleum ether, B = EtOAc; Gradient: 0-10% B over 15 min; Flow rate: 60 mL / min) to afford the title compound. ’H NMR (400 MHz, CDCl₃): δ = 7.82 (s, 1H), 7.37 (s, 1H), 3.91 (s, 3H), 2.32 (s, 3H).

[0248] Step 3: Synthesis of methyl 2-(bromomethyl)-6-iodo-4-(trifluoromethyl)benzoate

[0249] To a solution of methyl 2-iodo-6-methyl-4-(trifluoromethyl)benzoate (0.5 g, 1.45 mmol) in CCl₄ (6 mL) was added BPO (35.2 mg, 145 μmol) and NBS (285 mg, 1.6 mmol). The mixture was stirred at 80 °C for 12 h. The reaction mixture was quenched by addition of aqueous ammonium chloride (20 mL) at 20 °C, then diluted with water (20 mL) and extracted with DCM (2 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound. ’H NMR (400 MHz, CDCl₃): δ = 7.96 (s, 1H), 7.60 (s, 1H), 4.41 (s, 2H), 3.95 (s, 3H).

[0250] Step 4: Synthesis of methyl 2-(((3-carbamoyl-2-fluorophenyl)amino)methyl)-6-iodo- 4-(trifluoromethyl)benzoate

[0251] To a solution of methyl 2-(bromomethyl)-6-iodo-4-(trifluoromethyl)benzoate (0.4 g, 946 μmol) and 3-amino-2-fluorobenzamide (146 mg, 946 μmol) in acetonitrile (16 mL) was added DIEA (611 mg, 4.73 mmol). The mixture was stirred at 80 °C for 12 h and then concentrated under reduced pressure. The residue was purified by flash chromatography (Instrument: Biotage Isolera Prime; Column: 12 g SepaFlash® Silica Flash Column; MobileDB1 / 166057797.1Docket No. 133447-5010-WOphase: A = petroleum ether, B = EtOAc; Gradient: 50-60% B over 10 min; Flow rate: 20 mL / min) to afford the title compound. LC-MS (ESI+): m / z = 497.0 [M+H]+.

[0252] Step 5: Synthesis of 2-fluoro-3-(7-iodo-l-oxo-5-(trifluoromethyl)isoindolin-2- yl)benzamide

[0253] To a solution of methyl 2-(((3 -carbarn oyl-2-fluorophenyl)amino)methyl)-6-iodo-4- (trifluoromethyl)benzoate (53.6 mg, 108 μmol) in MeOH (2 mL) was added TEA (32.8 mg, 324 μmol). The mixture was stirred at 40 °C for 12 h and then concentrated under reduced pressure to afford the title compound. LC-MS (ESI+): m / z = 464.8 [M+H]+.

[0254] Synthesis of methyl 3-(7-bromo-l-oxoisoindolin-2-yl)-2,6-difluorobenzoate (Intermediate 1.8)

[0255] Step 1: Synthesis of methyl 3-((3-bromo-2-(methoxycarbonyl)benzyl)amino)-2,6- difluorobenzoate

[0256] To a solution of methyl 2-bromo-6-(bromomethyl)benzoate (1.5 g, 3.65 mmol, from Intermediate 1.2) and methyl 3-amino-2,6-difluorobenzoate (684 mg, 3.65 mmol) in MeCN (10 mL, 191 mmol) was added K₂CO₃ (1.01 g, 7.31 mmol). The mixture was stirred at 40 °C for 12 h. On completion, the reaction mixture was diluted by water (30 mL) and extracted by EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (Instrument: Biotage Isolera Prime; Column: 40 g SepaFlash® Silica Flash Column; Mobile phase: A = petroleum ether, B = EtOAc; Gradient: 0-50% B over 10 min; Flow rate: 40 mL / min) afford the title compound. LC-MS (ESI+): m / z = 415.8 [M+H]+.

[0257] Step 2: Synthesis of methyl 3-(7-bromo-l-oxoisoindolin-2-yl)-2,6-difluorobenzoate

[0258] To a solution of methyl 3-((3-bromo-2-(methoxycarbonyl)benzyl)amino)-2,6- di fluorobenzoate (420 mg, 1.01 mmol) in MeOH (9 mL, 222 mmol) was added triethylamine (205 mg, 2.03 mmol). The mixture was stirred at 40 °C for 5 h. On completion, the reactionDB1 / 166057797.1Docket No. 133447-5010-WOmixture was filtered, and the filter cake dried under vacuum to afford the title compound. LC- MS (ESI+) m / z = 382.1 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ = 7.92 (dt, J = 5.8, 8.8 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 7.2 Hz, 1H), 7.63–7.57 (m, 1H), 7.41 (dt, J = 1.6, 9.2 Hz, 1H), 4.90 (s, 2H), 3.93 (s, 3H).

[0259] Synthesis of methyl 3-(7-bromo-5-fluoro-l-oxoisoindolin-2-yl)benzoate (Intermediate 1.9)

[0260] Step 1: Synthesis of methyl 2-bromo-6-(bromomethyl)-4-fluorobenzoate

[0261] A solution of methyl 2-bromo-4-fluoro-6-m ethylbenzoate (31 g, 125 mmol) and N- bromosuccinimide (NBS; 24.6 g, 138 mmol) in acetonitrile (620 mL, 11.9 mol) was delivered via Pump 1 (5.0 mL / min)to Flow Reactor 1 (FLR1; Coil reactor: 3.175 mm (1 / 8”), 50.0 mL, 45 °C, 455 nm, 400 W; Residence time: 10 minutes). LC-MS analysis confirmed complete consumption of the starting material and formation of the desired product. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (2 x 500 mL), and the organic layer was washed with brine (2 x 300 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound. LC-MS (ESI⁺): m / z = 244.9 [M-Br+H]+. *H NMR (400 MHz, DMSO-d6): 67.71 (dd, J = 2.4, 8.4 Hz, 1H), 7.54 (dd, J = 2.4, 9.2 Hz, 1H), 4.63 (s, 2H), 3.91 (s, 3H).

[0262] Step 2: Synthesis of methyl 3-(7-bromo-5-fluoro-l-oxoisoindolin-2-yl)benzoate

[0263] To a solution of methyl 2-bromo-6-(bromomethyl)-4-fluorobenzoate (37 g, 114 mmol) in / V-methyl-2-pyrrolidone (NMP; 370 mL, 3.83 mol) was added methyl 3 -aminobenzoate (17.2 g, 114 mmol) at 20 °C. The reaction mixture was stirred at 80 °C for 4 hours. LC-MS analysis confirmed complete consumption of the starting material and the presence of the desired product. Water (1.00 L) was added to the mixture, and the resulting solid was collected by filtration. The crude product was triturated with a 3: 1 mixture of hexane and ethyl acetate (400 mL) at 20 °C for 2 hours. The solid was filtered and dried to afford the title compound. LC-MSDB1 / 166057797.1Docket No. 133447-5010-WO(ESI+): m / z = 363.9 [M+H]’.1H NMR (400 MHz, DMSO-de): 68.51 (br s, 1H), 8.07 (br s, 1H), 7.73 (br d, J = 15.2 Hz, 2H), 7.60 (br s, 2H), 5.02 (br s, 2H), 3.89 (br s, 3H).

[0264] Synthesis of methyl 3-(7-chloro-5-(oxetan-3-yl)-l-oxoisoindolin-2-yl)benzoate (Intermediate 1.10)$ a...

[0265] Step 1: Synthesis of methyl 4-bromo-2-chloro-6-methylbenzoate

[0266] To a solution of 4-bromo-2-chloro-6-methylbenzoic acid (10 g, 40.1 mmol) and K2CO3 (11.1 g, 80.2 mmol) in DMF (100 mL) was added iodomethane (11.4 g, 80.2 mmol) in one portion. The mixture was stirred at 20 °C for 2 hours. It was then diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 * 100 mL), dried over Na₂SO₄, filtered, and concentrated. The crude residue was purified by column chromatography (Stationary phase: Silica gel; Mobile phase: A = petroleum ether, B = EtOAc; Gradient: 0-50% B) to afford the title compound. LC-MS (ESI+): m / z = 263.1 [M+H]+.

[0267] Step 2: Synthesis of methyl 4-bromo-2-(bromomethyl)-6-chlorobenzoate

[0268] To a solution of methyl 4-bromo-2-chloro-6-methylbenzoate (9 g, 34.2 mmol) and BPO (1.65 g, 6.83 mmol) in CCl₄ (100 mL) was added NBS (6.69 g, 37.6 mmol) in one portion. The mixture was stirred at 80 °C for 2 hours, diluted with water (100 mL), and extracted with EtOAc (3 x 100 mL). The organic layers were washed with brine (2 x 100 mL), dried over Na₂SO₄, filtered, and concentrated. The crude residue was purified by column chromatography (Stationary phase: Silica gel; Mobile phase: A = petroleum ether, B = EtOAc; Gradient: 0-50% B) to afford the title compound. LC-MS (ESI+): m / z = 342.8 [M+H]+.DB1 / 166057797.1Docket No. 133447-5010-WO

[0269] Step 3: Synthesis of methyl 4-bromo-2-chloro-6-(((3- (methoxycarbonyl)phenyl)amino)methyl)benzoate

[0270] To a solution of methyl 4-bromo-2-(bromomethyl)-6-chlorobenzoate (10 g, 29.2 mmol) and methyl 3 -aminobenzoate (4.41 g, 29.2 mmol) in ACN (100 mL) was added K2CO3 (12.1 g, 87.6 mmol) in one portion. The mixture was stirred at 40 °C for 2 hours, diluted with water (100 mL), and extracted with EtOAc (3 x 100 mL). The organic layers were washed with brine (2 x 100 mL), dried over Na₂SO₄, filtered, and concentrated. The crude residue was purified by column chromatography (Stationary phase: Silica gel; Mobile phase: A = petroleum ether, B = EtOAc; Gradient: 10-100% B) to afford the title compound. LC-MS (ESI+): m / z = 413.8 [M+H]+.

[0271] Step 4: Synthesis of methyl 3-(5-bromo-7-chloro-l-oxoisoindolin-2-yl)benzoate

[0272] To a solution of methyl 4-bromo-2-chloro-6-(((3- (methoxycarbonyl)phenyl)amino)methyl)benzoate (8 g, 19.4 mmol) in MeOH (32 mL) was added TEA (5.89 g, 58.2 mmol). The mixture was stirred at 40 °C for 2 hours, then filtered and concentrated to afford the title compound. LC-MS (ESI+): m / z = 382.0 [M+H]+.1H NMR (400 MHz, DMSO-de): δ = 8.50 (br s, 1H), 8.09 (br d, J = 7.4 Hz, 1H), 7.92 (br s, 1H), 7.84 (br s, 1H), 7.78 (br d, J = 6.8 Hz, 1H), 7.60 (br t, J = 7.5 Hz, 1H), 5.03 (br s, 2H), 3.89 (br s, 3H).

[0273] Step 5: Synthesis of methyl 3-(7-chloro-5-(oxetan-3-yl)-l-oxoisoindolin-2- yl)benzoate

[0274] To a solution of methyl 3-(5-bromo-7-chloro-l-oxoisoindolin-2-yl)benzoate (0.3 g, 788 pmol), Ir(dF(CF₃)ppy)₂(dtbpy)(PF₆) (16.2 mg, 15.8 μmol), [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine] nickel (II) dichloride ((4,4′-dtbbpy)NiCl₂; 9.41 mg, 23.6 μmol), and K₂CO₃ (167 mg, 1.58 mmol) in DME (6 mL) was added 3-bromooxetane (216 mg, 1.58 mmol) and tris(trimethylsilyl)silane (TTMSS; 235 mg, 946 μmol) in one portion. The mixture was stirred at 20 °C for 12 hours under nitrogen atmosphere. The reaction was quenched by dropwise addition of aqueous NH₄Cl solution (10 mL), then extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over Na₂SO₄, filtered, and concentrated. The crude residue was purified by column chromatography (Stationary phase: Silica gel; Mobile phase: A = petroleum ether, B = EtOAc; Gradient: 0-100% B) to afford theDB1 / 166057797.1Docket No. 133447-5010-WOtitle compound. LC-MS (ESP): m / z = 357.9 [M+H]+.1H NMR (400 MHz, DMSO-ds): 8 = 8.62- 8.47 (m, 1H), 8.09 (br d, J = 7.0 Hz, 1H), 7.78 (br d, J = 6.8 Hz, 1H), 7.70 (br s, 1H), 7.65-7.52 (m, 2H), 5.10-4.93 (m, 4H), 4.67 (br s, 2H), 4.56-4.32 (m, 1H), 3.90 (br s, 3H).

[0275] Synthesis of 3-(7-bromo-5-fluoro-l-oxoisoindolin-2-yl)-A-methylbenzamide (Intermediate 1.11)BrI'

[0276] Step 1: Synthesis of methyl 2-bromo-4-fluoro-6-methylbenzoate

[0277] To a solution of 2-bromo-4-fluoro-6-methylbenzoic acid (5 g, 21.5 mmol) in DMF (50 mL) was added K2CO3 (4.45 g, 32.2 mmol) and iodomethane (6.09 g, 42.9 mmol, 2.0 eq.). The mixture was stirred at 20 °C for 2 hours. Upon completion, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (Instrument: Biotage Isolera Prime; Column: 80 g SepaFlash® Silica Flash Column; Mobile phase: A = petroleum ether, B = EtOAc; Gradient: 0-50% B over 10 min; Flow rate: 40 mL / min) to afford the title compound. LC-MS (ESP): m / z = 247.0 [M+H]~.1H NMR (400 MHz, DMSO-de): 8 = 7.49 (dd, J = 2.3, 8.4 Hz, 1H), 7.23 (dd, J = 1.9, 9.5 Hz, 1H), 3.87 (s, 3H), 2.27 (s, 3H).

[0278] Step 2: Synthesis of methyl 2-bromo-6-(bromomethyl)-4-fluorobenzoate

[0279] To a solution of methyl 2-bromo-4-fluoro-6-methylbenzoate (1.55 g, 6.27 mmol) in anhydrous CCL (20 mL) was added AIBN (103 mg, 627 pmol) and NBS (1.34 g, 7.53 mmol) at 0 °C under nitrogen. The reaction mixture was stirred at 90 °C for 20 hours. Upon completion, the mixture was concentrated in vacuo. The crude product was purified by flash chromatography (Instrument: Biotage Isolera Prime; Column: 20 g SepaFlash® Silica Flash Column; MobileDB1 / 166057797.1Docket No. 133447-5010-WOphase: A = petroleum ether, B = EtOAc; Gradient: 0-20% B over 10 min; Flow rate: 25 mL / min) to afford the title compound. LC-MS (ESI+): m / z = 326.9 [M+H]+.

[0280] Step 3: Synthesis of methyl 2-bromo-4-fluoro-6-(((3- (methylcarbamoyl)phenyl)amino)methyl)benzoate

[0281] To a solution of methyl 2-bromo-6-(bromomethyl)-4-fluorobenzoate (1.5 g, 4.6 mmol) and 3 -amino - / V-m ethylbenzamide (760 mg, 5.06 mmol) in MeCN (15 mL) was added K₂CO₃ (1.27 g, 9.2 mmol). The mixture was stirred at 40 °C for 2 hours. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by prep- HPLC (Instrument: Biotage Isolera Prime; Column: Phenomenex Luna C18, 150 × 25 mm, 10 pm; Mobile phase: A = water (0.1% TFA), B = acetonitrile; Gradient: 20-70% B over 10 min; Flow rate: 30 mL / min) to afford the title compound. LC-MS (ESU): m / z = 395.1 [M+H]+.

[0282] Step 4: Synthesis of 3-(7-bromo-5-fluoro-l-oxoisoindolin-2-yl)- / V-methylbenzamide

[0283] To a solution of methyl 2-bromo-4-fluoro-6-(((3- (methylcarbamoyl)phenyl)amino)methyl)benzoate (1.5 g, 3.8 mmol) in MeOH (15 mL) was added TEA (931 mg, 9.2 mmol). The reaction mixture was stirred at 40 °C for 5 hours. Upon completion, the reaction was filtered and the filtrate was concentrated in vacuo to afford the title compound. LC-MS (ESI+): m / z = 364.9 [M+H]*. ‘HNMR (400 MHz, DMSO-de): 5 = 8.48 (br d, J = 4.4 Hz, 1H), 8.21 (s, 1H), 8.07 (dd, J = 1.6, 8.0 Hz, 1H), 7.71 (dd, J = 2.0, 9.0 Hz, 1H), 7.63 (t, J = 8.4 Hz, 2H), 7.55-7.48 (m, 1H), 5.01 (s, 2H), 2.81 (d, J = 4.8 Hz, 3H).

[0284] Synthesis of 3-(4-bromo-3-oxo-l,3-dihydro-2 / / -pyrrolo[3,4-c]pyridin-2-yl)-Ar- methylbenzamide (Intermediate 1.12)til o6 ''

[0285] Step 1: Synthesis of ethyl 2-bromo-4-(bromomethyl)nicotinate

[0286] A solution of ethyl 2-bromo-4-methylnicotinate (3 g, 12.3 mmol), N- Bromosuccinimide (NBS; 4.38 g, 24.6 mmol, 2 eq.), 2-(1-cyano-1-methylethylazo)-2-methylpropiononitrile (202 mg, 1.23 mmol, 0.1 eq.), and acetic acid (738 mg, 12.3 mmol) in carbon tetrachloride (40 mL) was stirred for 12 h at 80 °C. Upon completion, water (50 mL) was DB1 / 166057797.1Docket No. 133447-5010-WOadded to the mixture and extracted with EtOAc (3 x 30 mL). Combined organic extracts were washed with brine (150 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (Instrument: Biotage Isolera Prime; Column: 40 g SepaFlash® Silica Flash Column; Mobile phase: A = petroleum ether, B = EtOAc; Gradient: 0- 10% B over 15 min; Flow rate: 60 mL / min) to afford the title compound. LC-MS (ESI+): m / z = 324.0 [M+H]+.

[0287] Step 2: Synthesis of 3-(4-bromo-3-oxo-l,3-dihydro-2 / / -pyrrolo[3,4-c]pyridin-2-yl)- JV-methy lb enzami de

[0288] To a solution of ethyl 2-bromo-4-(bromomethyl)ni cotinate (1.2 g, 1.86 mmol) in acetonitrile (10 mL) was added A-ethyldiisopropylamine (480 mg, 3.72 mmol, 2 eq.) and 3- amino-A-methylbenzamide (307 mg, 2.04 mmol, 1.1 eq.). The mixture was stirred at 100 °C for 12 h. Upon completion, the solid was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure to afford the title compound. LC-MS (ESI+): m / z = 348.0 [M+H]+.1H NMR (400 MHz, DMSO-de): δ = 8.60 (d, J = 5.2 Hz, 1H), 8.51 (br d, J = 4.4 Hz, 1H), 8.23 (t, J = 1.6 Hz, 1H), 8.12–8.06 (m, 1H), 7.81 (d, J = 5.2 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.58–7.47 (m, 1H), 5.11 (s, 2H), 2.81 (d, J = 4.4 Hz, 3H).

[0289] Synthesis of 3-(7-bromo- 1-oxo- 1, 3-dihydro-2 / 7-pyrrolo[3,4-c]pyri din-2 -yl)-7V- methylbenzamide (Intermediate 1.13)

[0290] Step 1: Synthesis of ethyl 3-bromo-5-(bromomethyl)isonicotinate

[0291] A solution of ethyl 3-bromo-5-methylisonicotinate (0.5 g, 2.05 mmol), N- bromosuccinimide (474 mg, 2.66 mmol, 1.3 eq.), and AIBN (168 mg, 1.02 mmol, 0.5 eq.) in CCL (10 mL) was stirred at 80 °C for 16 h. LC-MS showed detection of the desired mass. The reaction was quenched with DCM (30 mL) and water (10 mL), and the layers were separated. The aqueous layer was extracted with DCM (2 x 10 mL), and the combined organic layers were washed with brine (30 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (Instrument: Biotage Isolera Prime; Column: 12 gDB1 / 166057797.1Docket No. 133447-5010-WOSepaFlash® Silica Flash Column; Mobile phase: A = hexane, B = EtOAc; Gradient: 0-10% B over 15 min; Flow rate: 60 mL / min) to afford the title compound. LC-MS (ESI+): m / z = 321.9 [M+H]+.

[0292] Step 2: Synthesis of ethyl 3-bromo-5-(((3-(methylcarbamoyl)phenyl)amino)methyl) isonicotinate

[0293] To a solution of ethyl 2-bromo-4-(bromomethyl)ni cotinate (1.2 g, 1.34 mmol) in acetonitrile (7.2 mL) was added 3-amino-A-methylbenzamide (221 mg, 1.47 mmol, 1.1 eq.) and JV-ethyldiisopropylamine (346 mg, 2.68 mmol, 2 eq.). The reaction was stirred at 80 °C for 3 h and then concentrated under reduced pressure. The residue was purified by flash chromatography (Instrument: Biotage Isolera Prime; Column: 20 g SepaFlash® Silica Flash Column; Mobile phase: A = hexane, B = EtOAc; Gradient: 0-100% B over 15 min; Flow rate: 60 mL / min) to afford the title compound. LC-MS (ESC): m / z = 392.1 [M+H]+.1H NMR (400 MHz, DMSO-ds): 5 = 8.76 (s, 1H), 8.67 (s, 1H), 8.25-8.12 (m, 2H), 7.16-7.09 (m, 1H), 6.91 (d, J = 7.6 Hz, 1H), 6.68-6.66 (m, 1H), 6.42 (br t, J = 5.6 Hz, 1H), 4.39-4.23 (m, 4H), 2.73 (d, J = 1.8 Hz, 3H), 1.24 (t, J = 7.2 Hz, 3H).

[0294] Step 3: Synthesis of 3-(7-bromo-l-oxo-l,3-dihydro-2 / 7-pyrrolo[3,4-c]pyridin-2-yl)- / V- m ethyl b enzami de

[0295] To a solution of ethyl 3-bromo-5-(((3-(methylcarbamoyl)phenyl)amino)methyl) isonicotinate (0.3 g, 765 pmol) in methanol (3 mL) was added triethylamine (155 mg, 1.53 mmol, 2 eq.). The mixture was stirred at 40 °C for 2 h. The mixture was concentrated under reduced pressure to afford the title compound. LC-MS (ESC): m / z = 346.0 [M+H]+.

[0296] Synthesis of 3-(4-chloro-5-oxo-5,7-dihydro-6 / / -pyrrolo[3,4-b]pyridin-6-yl)-7V- methylbenzamide (Intermediate 1.14)T t a s...

[0297] Step 1: Synthesis of methyl 2-(bromomethyl)-4-chloronicotinateDB1 / 166057797.1Docket No. 133447-5010-WO

[0298] To a solution of methyl 4-chloro-2-methylnicotinate (1.8 g, 9.7 mmol) in CCl₄ (36 mL) were added N-bromosuccinimide (2.24 g, 12.6 mmol,) and AIBN (159 mg, 970 pmol) under nitrogen at 20 °C. The mixture was stirred at 90 °C for 12 h. The reaction was quenched with water (20 mL) and extracted with DCM (3 x 20 mL). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (Instrument: Biotage Isolera Prime; Column: 20 g SepaFlash® Silica Flash Column; Mobile phase: A = hexane, B = EtOAc; Gradient: 0-5% B over 4 min; Flow rate: 80 mL / min) to afford the title compound. LC-MS (ESC): m / z = 263.8 [M+H]+. ’H NMR (400 MHz, MeOH-d4): 5 = 8.53 (d, J = 5.6 Hz, 1H), 7.55 (d, J = 5.6 Hz, 1H), 4.63 (s, 2H), 4.00 (s, 3H).

[0299] Step 2: Synthesis of methyl 4-chloro-2-(((3-(methylcarbamoyl)phenyl)amino)methyl) nicotinate

[0300] To a solution of methyl 2-(bromomethyl)-4-chloronicotinate (0.7 g, 2.65 mmol) and 3-amino-A-methylbenzamide (397 mg, 2.65 mmol) in acetonitrile (10 mL) was added N- ethyldiisopropylamine (684 mg, 5.29 mmol, 2 eq.) at 20 °C. The reaction was stirred at 100 °C for 12 h under nitrogen. The mixture was concentrated under reduced pressure and purified by flash chromatography (Instrument: Biotage Isolera Prime; Column: 20 g SepaFlash® Silica Flash Column; Mobile phase: A = hexane, B = EtOAc; Gradient: 0-80% B over 10 min; Flow rate: 80 mL / min) to afford the title compound. LC-MS (ESC): m / z = 334.1 [M+H]+. ’H NMR (400 MHz, MeOH-d4) 8 = 8.51 (d, J = 5.6 Hz, 1H), 7.48 (d, J = 5.6 Hz, 1H), 7.17-7.13 (m, 1H), 7.06-7.01 (m, 2H), 6.72 (dd, J = 2.0, 8.0 Hz, 1H), 4.52 (s, 2H), 3.85 (s, 3H), 2.88-2.86 (m, 3H).

[0301] Step 3: Synthesis of 3-(4-chloro-5-oxo-5,7-dihydro-677-pyrrolo[3,4-b]pyridin-6-yl)- JV-methylbenzamide

[0302] To a solution of methyl 4-chloro-2-(((3-(methylcarbamoyl)phenyl)amino)methyl) nicotinate (780 mg, 2.34 mmol) in methanol (6 mL) was added triethylamine (473 mg, 4.67 mmol, 2 eq.) at 20 °C. The reaction was stirred at 40 °C for 2 h. The mixture was concentrated under reduced pressure to afford the title compound. LC-MS (ESC): m / z = 302.1 [M+H]+.

[0303] Synthesis of l-(3-(7-bromo-l-oxoisoindolin-2-yl)phenyl)-3-methylurea (Intermediate 1.15)DB1 / 166057797.1Docket No. 133447-5010-WO& %t

[0304] Step 1: Synthesis of methyl 2-bromo-6-(((3-(( / er / -butoxycarbonyl)amino)phenyl) amino)methyl)benzoate

[0305] To a mixture of tert-butyl (3 -aminophenyl )carbamate (0.5 g, 2.4 mmol) and K2CO3 (664 mg, 4.8 mmol) in ACN (5 mL) was added methyl 2-bromo-6-(bromomethyl)benzoate (1.11 g, 3.6 mmol, from Intermediate 1.2). The mixture was stirred at 60 °C for 16 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to afford the title compound. LC-MS (ESI+): m / z = 436.8 [M+H]+.

[0306] Step 2: Synthesis of tert-butyl (3-(7-bromo-l-oxoisoindolin-2-yl)phenyl)carbamate

[0307] To a solution of methyl 2-bromo-6-(((3-((tert-butoxycarbonyl)amino)phenyl)amino) methyl)benzoate (1.0 g, 2.3 mmol) in MeOH (10 mL) was added TEA (465 mg, 4.59 mmol). The mixture was stirred at 60 °C for 4 h under N2. The mixture was filtered, and the filtrate was concentrated under reduced pressure to afford the title compound. LC-MS (ESI+): m / z = 403.1 [M+H]+. ’HNMR(400 MHz, DMSO-de): 8 = 9.44 (s, 1H), 8.14 (s, 1H), 7.75-7.64 (m, 2H), 7.60-7.52 (m, 1H), 7.51-7.44 (m, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.20 (br d, J = 8.4 Hz, 1H), 4.93 (s, 2H), 1.49 (s, 9H).

[0308] Step 3: Synthesis of 2-(3-aminophenyl)-7-bromoisoindolin-l-one

[0309] To a solution of tert-butyl (3-(7-bromo-l-oxoisoindolin-2-yl)phenyl)carbamate (450 mg, 1.12 mmol) in DCM (6 mL) was added TFA (1 mL). The mixture was stirred at 25 °C for 1 h, then concentrated under reduced pressure to afford the title compound. LC-MS (ESI+): m / z = 303.1 [M+H]+.

[0310] Step 4: Synthesi s of 1 -(3 -(7 -bromo- 1 -oxoi soindolin-2-yl)pheny l)-3 -methylureaDB1 / 166057797.1Docket No. 133447-5010-WO

[0311] To a solution of 2-(3-aminophenyl)-7-bromoisoindolin-l-one (0.3 g, 990 pmol) in DCM (3 mL) was added TEA (92.5 mg, 990 pmol) under N2 at 0 °C, followed by addition of N- methylcarbamoyl chloride (92.5 mg, 990 pmol). The reaction was stirred at 25 °C for 16 h. The reaction mixture was filtered and the solid was dried under reduced pressure to afford the title compound. LC-MS (ESI+): m / z = 360.0 [M+H]*. ‘HNMR (400 MHz, DMSO-de): 6 = 8.78 (br s, 1H), 8.02 (s, 1H), 7.74-7.65 (m, 2H), 7.60-7.52 (m, 1H), 7.39-7.35 (m, 1H), 7.28-7.22 (m, 2H), 6.11 (br s, 1H), 4.93 (s, 2H), 2.65 (d, J = 4.4 Hz, 3H).

[0312] Synthesis of 3-(7-bromo-l-oxoisoindolin-2-yl)benzamide (Intermediate 1.16)

[0313] Step 1: Synthesis of methyl 2-bromo-6-(((3-carbamoylphenyl)amino)methyl)benzoate

[0314] To a solution of methyl 2-bromo-6-(bromomethyl)benzoate (4 g, 13 mmol, from Intermediate 1.2) and 3-aminobenzamide (1.77 g, 13 mmol) in MeCN (40 mL) was added N- ethyldiisopropylamine (5.04 g, 39 mmol, 3 eq.). The mixture was stirred at 80 °C for 3 hours and then concentrated under reduced pressure to afford the title compound. LC-MS (ESI+): m / z = 363.0 [M+H]+.

[0315] Step 2: Synthesis of 3-(7-bromo-l-oxoisoindolin-2-yl)benzamide

[0316] To a solution of methyl 2-bromo-6-(((3-carbamoylphenyl)amino)methyl)benzoate (4 g, 11 mmol) in MeOH (40 mL) was added triethylamine (3.34 g, 33 mmol, 3 eq.). The mixture was stirred at 80 °C for 5 hours. After completion, the mixture was filtered and the fdter cake was washed with MeOH (30 mL). The combined fdtrate was concentrated under reduced pressure to afford the title compound. LC-MS (ESI+): m / z = 333.0 [M+H]+. 'HNMR (400 MHz, DMSO-de): 5 = 8.25 (s, 1H), 8.18-8.09 (m, 1H), 8.06-7.99 (m, 1H), 7.77-7.66 (m, 3H), 7.64- 7.49 (m, 2H), 7.44 (br s, 1H), 5.04 (s, 2H).

[0317] Synthesis of / V-(3-(7-bromo-l-oxoisoindolin-2-yl)phenyl)acetamide (Intermediate 1.17)DB1 / 166057797.1Docket No. 133447-5010-WO

[0318] Step 1: Synthesis of A-(3-(7-bromo-l-oxoisoindolin-2-yl)phenyl)acetamide

[0319] To a solution of / V-(3-aminophenyl)acetamide (0.2 g, 1.33 mmol) in ACN (4 mL) was added methyl 2-bromo-6-(bromomethyl)benzoate (615 mg, 2 mmol, from Intermediate 1.2) and K2CO3 (368 mg, 2.66 mmol) in one portion. The mixture was stirred at 60 °C for 2 h. Upon completion, the mixture was filtered, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (Instrument: Biotage Isolera Prime; Column: 12 g SepaFlash® Silica Flash Column; Mobile phase: A = hexane, B = EtOAc; Gradient: 40-50% B over 10 min; Flow rate: 60 mL / min) to afford the title compound. LC-MS (ESI+): m / z = 347.1 [M+H]+.1HNMR(400 MHz, DMSO-de): 8 = 10.05 (s, 1H), 8.23 (s, 1H), 7.70 (dd, J = 7.6, 14.0 Hz, 2H), 7.61-7.54 (m, 1H), 7.47 (br d, J = 8.0 Hz, 2H), 7.38-7.29 (m, 1H), 4.94 (s, 2H), 2.06 (s, 3H).

[0320] Synthesis of 3-(4-bromo-l,l-dimethyl-3-oxoisoindolin-2-yl)-A-methylbenzamide (Intermediate 1.18)>••••<>« •

[0321] Step 1: Synthesis of 3-(4-bromo-l,l-dimethyl-3-oxoisoindolin-2-yl)benzoic acid

[0322] A mixture of methyl 3-(7-bromo-l-oxoisoindolin-2-yl)benzoate (0.5 g, 1.44 mmol, from Intermediate 1.1) in DMF (5 mL) and THF (5 mL) was added sodium hydride (NaH, 60% in mineral oil; 578 mg, 14.4 mmol) slowly at 0 °C. The mixture was stirred at 20 °C for 3 hours. Then Mel (820 mg, 5.78 mmol) was added dropwise at 0 °C, and the mixture was stirred at 25 °C for 0.5 hours. The reaction was quenched with H2O (3 mL) at 0 °C, diluted with H2O (50 mL), and extracted with EtOAc (3 * 30 mL). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (Instrument: Biotage Isolera Prime; Column: 120 g SepaFlash® Silica Flash Column; Mobile phase: A = DCM, B = EtOAc; Gradient: 0-55% B over 160 min; Flow rate: 100 mL / min) to afford the title compound. LC-MS (ESI+): m / z = 362.0DB1 / 166057797.1Docket No. 133447-5010-WO[M+H]+. ¹H NMR (400 MHz, DMSO-d₆): 8 = 13.17 (br s, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.84 (s, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.72-7.64 (m, 2H), 7.63-7.57 (m, 2H), 1.48 (s, 6H).

[0323] Step 2: Synthesis of 3-(4-bromo-l,l-dimethyl-3-oxoisoindolin-2-yl)-A- methylbenzamide

[0324] To a solution of 3-(4-bromo-l,l-dimethyl-3-oxoisoindolin-2-yl)benzoic acid (0.1 g, 278 pmol), methylamine hydrochloride (37.5 mg, 555 pmol), andDIEA (108 mg, 833 pmol) in DMF (6 mL) was added HATU (137 mg, 361 pmol). The mixture was stirred at 50 °C for 2 hours after which the mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (Instrument: Gilson 281 + Shimadzu LC-20AP; Column: WePure Biotech XPT C18, 150 × 25 mm, 7 pm; Mobile phase: A = water (10 mM NH₄HCO₃), B = acetonitrile;Gradient: 5-45% B over 15 min; Flow rate: 60 mL / min) to afford the title compound. LC-MS (ESC): m / z = 373.1 [M+H]’.

[0325] Synthesis of 3-(4-bromo-l-methyl-3-oxoisoindolin-2-yl)-A-methylbenzamide (Intermediate 1.19)

[0326] Step 1: Synthesis of methyl 3-(4-bromo-l-methyl-3-oxoisoindolin-2-yl)benzoate

[0327] To a solution of methyl 3-(7-bromo-l-oxoisoindolin-2-yl)benzoate (1.0 g, 2.89 mmol, from Intermediate 1.1) in DMF (10 mL) was added sodium hydride (NaH, 60% in mineral oil; 173 mg, 4.33 mmol) at 0 °C under N2. The mixture was stirred at 0 °C for 30 min, followed by addition of Mel (328 mg, 2.31 mmol). The mixture was stirred for 30 min at 0 °C under N2. The reaction mixture was quenched with saturated NH4CI (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (Instrument: Biotage Isolera Prime; Column: 12 g SepaFlash® Silica Flash Column; Mobile phase: A = hexane, B = EtOAc; Gradient: 0-50% B over 5 min; Flow rate: 80 mL / min) to afford the title compound. LC-MS (ESI+): m / z = 360.0 [M+H]+.1H NMR (400 MHz, DMSO-ds): 8 =DB1 / 166057797.1Docket No. 133447-5010-WO8.31 (s, 1H), 7.90-7.83 (m, 2H), 7.75 (dd, J = 1.6, 7.6 Hz, 2H), 7.65-7.60 (m, 2H), 5.53 (q, J = 6.4 Hz, 1H), 3.89 (s, 3H), 1.37 (d, J = 6.4 Hz, 3H).

[0328] Step 2: Synthesis of 3-(4-bromo-l-methyl-3-oxoisoindolin-2-yl)benzoic acid

[0329] To a solution of methyl 3-(4-bromo-l-methyl-3-oxoisoindolin-2-yl)benzoate (0.4 g, 1.11 mmol) in THF (5 mL) and H2O (1 mL) was added NaOH (222 mg, 5.55 mmol). The mixture was stirred at 20 °C for 12 h, then adjusted to pH 3 with 1 M HC1. The aqueous phase was extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (Instrument: Gilson 281 + Shimadzu LC-20AP; Column: Welch Ultimate C18, 150 × 25 mm, 7 pm; Mobile phase: A = water (0.1% NH4HCO3), B = acetonitrile; Gradient: 10-30% B over 5 min; Flow rate: 60 mL / min) to afford the title compound. LC-MS (ESI+): m / z = 345.9 [M+H]+.

[0330] Step 3: Synthesis of 3-(4-bromo-l-methyl-3-oxoisoindolin-2-yl)-A-methylbenzamide

[0331] To a solution of 3-(4-bromo-l-methyl-3-oxoisoindolin-2-yl)benzoic acid (0.3 g, 867 pmol) and methylamine hydrochloride (58.5 mg, 867 pmol) in DMF (3 mL) was added HATU (494 mg, 1.3 mmol) and DIEA (560 mg, 4.33 mmol). The mixture was stirred at 20 °C for 1 h after which the mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (Instrument: Biotage Isolera Prime; Column: Phenomenex Luna C18, 150 × 25 mm, 10 μm; Mobile phase: A = water (0.1% formic acid), B = acetonitrile; Gradient: 30-50% B over 10 min; Flow rate: 40 mL / min) followed by prep-SFC (Instrument: Waters 150AP; Column: Chiralcel OD, 250 x 30 mm, 10 pm; Mobile phase: A = CO2, B = methanol (0.1% ammonium hydroxide); Gradient: 4-40% B over 10 min; Flow rate: 10 mL / min; Pressure: 100 bar; Temperature: 35 °C) to afford the title compound. LC-MS (ESI+): m / z = 360.9 [M+H]+. ’H NMR (400 MHz, DMSO-de): 5 = 8.50 (br d, J = 4.0 Hz, 1H), 8.06 (s, 1H), 7.82-7.69 (m, 4H), 7.64-7.53 (m, 2H), 5.48 (q, J = 6.4 Hz, 1H), 2.81 (d, J = 4.4 Hz, 3H), 1.36 (d, J = 6.4 Hz, 3H).

[0332] Synthesis of methyl 3-(4-bromo-3-oxo-l-(2-((tetrahydro-2 / 7-pyran-2- yl)oxy)ethyl)isoindolin-2-yl)benzoate (Intermediate 1.20)o.r F X JDB1 / 166057797.1Docket No. 133447-5010-WO

[0333] Step 1: Synthesis of methyl 3-(4-bromo-3-oxo-l-(2-((tetrahydro-2 / f-pyran-2- yl)oxy)ethyl)isoindolin-2-yl)benzoate

[0334] To a solution of methyl 3-(7-bromo-l-oxoisoindolin-2-yl)benzoate (1 g, 2.89 mmol, from Intermediate 1.1) in DMF (10 mL) was added sodium hydride (NaH, 60% in mineral oil; 173 mg, 4.33 mmol) at 0 °C under N?. The mixture was stirred at 0 °C for 0.5 h. Then 2-(2- iodoethoxy)tetrahydro-27 / -pyran (888 mg, 3.47 mmol) was added at 0 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into saturated NFkCl aqueous solution (30 mL) and extracted with EA (3 x 20 mL). The combined organic layer was washed with brine (15 mL), dried over Na2SCL, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Instrument: Biotage Isolera Prime; Column: 12 g SepaFlash® Silica Flash Column; Mobile phase: A = hexane, B = EtOAc; Gradient: 0-50% B over 15 min; Flow rate: 60 mL / min) to afford the title compound. LC-MS (ESI⁺): m / z = 496.1 [M+Na]+.

[0335] Synthesis of methyl 3-(4-bromo-l-methylene-3-oxoisoindolin-2-yl)benzoate (Intermediate 1.21)

[0336] Step 1: Synthesis of methyl 3-(4-bromo-l-methylene-3-oxoisoindolin-2-yl)benzoate

[0337] A suspension of methyl 3-(7-bromo-l-oxoisoindolin-2-yl)benzoate (1 g, 2.89 mmol, from Intermediate 1.1) in DMF (10 mL), was purged with N2 and cooled to 0 °C before sodium hydride (NaH, 60% in mineral oil; 254 mg, 6.36 mmol) was added. The mixture was stirred at 0 °C for 1 h. Then benzyl chloromethyl ether (797 pL, 5.78 mmol) in DMF (5 mL) was added dropwise. The reaction was stirred at 0-20 °C for 1 h and then at 45 °C for 12 h. On completion, the reaction was quenched by 100 mL sat. NH4Q and extracted with EA (2 x 100 mL). The combined organic layer was washed with brine (2 x 100 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (Instrument: Biotage Isolera Prime; Column: 40 g SepaFlash® Silica Flash Column; Mobile phase: A = hexane, B = EtOAc; Gradient: 0-17% B over 10 min; Flow rate: 120 mL / min) to afford the title compound. LC-MS (ESI+): m / z = 359.9 [M+H]+. ¹H NMR (400 MHz, DMSO-d₆): 8 = 8.12 (d, J = 7.6 Hz, 1H), 8.06 (dt, J = 1.6, 4.5 Hz, 1H), 7.86-7.82 (m, 1H), 7.74 (br d, J = 1.6 DB1 / 166057797.1Docket No. 133447-5010-WOHz, 1H), 7.69-7.65 (m, 1H), 7.25 (br s, 2H), 5.61 (d, J = 2.4 Hz, 1H), 4.76 (d, J = 2.4 Hz, 1H), 3.89 (s, 3H).

[0338] Synthesis of 3-(7-ethynyl-1-oxoisoindolin-2-yl)-N-methylbenzamide (Intermediate 1.22)- -\--Q

[0339] Step 1: Synthesis of methyl 3-(l-oxo-7-((trimethylsilyl)ethynyl)isoindolin-2- yl)benzoate

[0340] To a solution of methyl 3-(7-bromo-l-oxoisoindolin-2-yl)benzoate (2.2 g, 6.36 mmol, from Intermediate 1.1), trimethylsilylacetylene (3.12 g, 31.8 mmol), Cui (40.4 mg 636 pmol), Pd(PPh3)2C12 (1.48 g, 1.91 mmol), and triethylamine (4.33 mL, 31.8 mmol) in DMF (22 mL, 284 mmol) was stirred at 80 °C for 2 h under nitrogen. The reaction mixture was poured into H₂O (40 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (Instrument: Biotage Isolera Prime; Column: 20 g SepaFlash® Silica Flash Column; Mobile phase: A = hexane, B = EtOAc; Gradient: 0-50% B over 10 min; Flow rate: 60 mL / min) to afford the title compound. LC-MS (ESI+): m / z = 364.2 [M+H]+.

[0341] Step 2: Synthesis of 3-(7-ethynyl-l-oxoisoindolin-2-yl)benzoic acid

[0342] To a solution of methyl 3-(l-oxo-7-((trimethylsilyl)ethynyl)isoindolin-2-yl)benzoate (1.27 g, 3.49 mmol) in tetrahydrofuran (8 mL, 98.3 mmol), methanol (8 mL, 197 mmol), and water (8 mL, 444 mmol) was added lithium hydroxide monohydrate (733 mg, 17.5 mmol) at 25 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure, poured into H₂O (20 mL), and extracted with EA (3 x 20 mL). The aqueous phase was adjusted to pH = 5 with 1 N HC1, filtered, and concentrated under reduced pressure to afford the title compound. LC-MS (ESI+): m / z = 278.0 [M+H]+.

[0343] Step 3: Synthesis of 3-(7-ethynyl-l-oxoisoindolin-2-yl)-7V-methylbenzamideDB1 / 166057797.1Docket No. 133447-5010-WO

[0344] To a solution of 3-(7-ethynyl-l-oxoisoindolin-2-yl)benzoic acid (850 mg, 3.07 mmol) in dimethylformamide (9 mL, 116 mmol) was added HATU (1.52 g, 3.99 mmol). The mixture was stirred at 20 °C for 0.5 h before A-ethyldiisopropylamine (1.6 mL, 9.2 mmol) and methylamine hydrochloride (621 mg, 9.2 mmol) were added. The mixture was stirred for an additional 1 h. The mixture was diluted with H2O (20 mL) and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over Na₂SO₄, filtered, and concentrated to afford the title compound. LC-MS (ESI+): m / z = 291.1 [M+H]+. ’HNMR (400 MHz, DMSO-de): 5 = 8.50 (br d, J = 4.0 Hz, 1H), 8.26 (s, 1H), 8.12 (dd, J = 1.2, 8.0 Hz, 1H), 7.76-7.57 (m, 4H), 7.56-7.48 (m, 1H), 5.03 (s, 2H), 4.54 (s, 1H), 2.81 (d, J = 4.4 Hz, 3H).

[0345] Synthesis of 3-(7-ethynyl-5-fluoro-l-oxoisoindolin-2-yl)-A-methylbenzamide (Intermediate 1.23)t?. I!y. ' Xi> G.Ci

[0346] Step 1: Synthesis of 3-(5-fluoro-l-oxo-7-((trimethylsilyl)ethynyl)isoindolin-2-yl)-7V- methylbenzamide

[0347] To a solution of 3-(7-bromo-5-fluoro-l-oxoisoindolin-2-yl)-X-methylbenzamide (1.5 g, 4.13 mmol, from Intermediate 1.11) and trimethylsilylacetylene (2.03 g, 20.7 mmol) in THF (13.7 mL) were added Pd(dppf)2C12 (604 mg, 826 pmol), TEA (2.09 g, 20.7 mmol), and Cui (262 mg, 826 pmol) in one portion. The mixture was stirred at 60 °C for 2 h under N₂ atmosphere and concentrated under reduced pressure. The residue was triturated with 60 mL aqueous NH4Q solution for 1 h, filtered, and dried under reduced pressure to afford the title compound. LC-MS (ESI+): m / z = 381.6 [M+H],

[0348] Step 2: Synthesis of 3-(7-ethynyl-5-fluoro-l-oxoisoindolin-2-yl)-7V-methylbenzamide

[0349] To a solution 3-(5-fluoro-l-oxo-7-((trimethylsilyl)ethynyl)isoindolin-2-yl)- / V- methylbenzamide (1.5 g, 3.94 mmol) in MeOH (20 mL) was added K2CO3 (1.63 g, 11.8 mmol) in one portion. The mixture was stirred at 20 °C for 2 h under N₂ atmosphere and concentrated under reduced pressure. The residue was triturated with 100 mL aqueous NH4CI solution for 1 h,DB1 / 166057797.1Docket No. 133447-5010-WOfiltered, and dried under reduced pressure to afford the title compound. LC-MS (ESI+): m / z = 309.1 [M+H]+.

[0350] Synthesis of 3-(7-ethynyl-5-fluoro-l-oxoisoindolin-2-yl)benzamide (Intermediate 1.24)

[0351] Step 1: Synthesis of methyl 2-bromo-6-(((3-carbamoylphenyl)amino)methyl)-4- fluorobenzoate

[0352] To a solution of methyl 2-bromo-6-(bromomethyl)-4-fluorobenzoate (7 g, 21.5 mmol, from Intermediate 1.9) and 3-aminobenzamide (2.9 g, 21.5 mmol) in ACN (100 mL) was added DIEA (13.9 g, 107 mmol). The mixture was stirred at 80 °C for 4 h and then concentrated under reduced pressure to afford the title compound. LC-MS (ESI+): m / z = 380.9 [M+H]+.

[0353] Step 2: Synthesis of 3-(7-bromo-5-fluoro-l-oxoisoindolin-2-yl)benzamide

[0354] To a solution of methyl 2-bromo-6-(((3-carbamoylphenyl)amino)methyl)-4- fluorobenzoate in MeOH (114 mL) was added TEA (6.37 g, 63 mmol). The mixture was stirred at 40 °C for 12 h. The reaction mixture was filtered, and the filter cake was dried under reduced pressure to afford the title compound. LC-MS (ESI+): m / z = 349.0 [M+H]+. 'HNMR (400 MHz, DMSO-de): 5 = 8.22 (s, 1H), 8.15-8.10 (m, 1H), 8.05 (s, 1H), 7.76-7.68 (m, 2H), 7.63 (d, J = 8.0 Hz, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.45 (s, 1H), 5.03 (s, 2H).

[0355] Step 3: Synthesis of 3-(5-fluoro-l-oxo-7-((trimethylsilyl)ethynyl)isoindolin-2- yl)benzamide

[0356] To a solution of 3-(7-bromo-5-fluoro-l-oxoisoindolin-2-yl)benzamide (2.2 g, 6.3 mmol) in DMSO (17.6 mL) was added Pd(PPh3)2Cl2 (442 mg, 630 pmol), Cui (240 mg,DB1 / 166057797.1Docket No. 133447-5010-WO1.26 mmol), TEA (6.38 g, 63 mmol) and ethynyltrimethylsilane (4.95 g, 50.4 mmol) under N₂ atmosphere. The suspension was degassed and purged with N2 (x3). The mixture was stirred at 60 °C for 1 h under N2. The mixture was triturated with H₂O at 20 °C for 10 min, and then filtered and dried under reduced pressure to afford the title compound. LC-MS (ESI+): m / z = 367.1 [M+H]+.

[0357] Step 4: Synthesis of 3-(7-ethynyl-5-fluoro-l-oxoisoindolin-2-yl)benzamide

[0358] To a solution of 3-(5-fluoro-l-oxo-7-((trimethylsilyl)ethynyl)isoindolin-2- yl)benzamide (0.9 g, 2.28 mmol) in methanol (10 mL, 247 mmol) was added dipotassium carbonate (946 mg, 3 eq., 6.84 mmol). The mixture was stirred at 20 °C for 0.5 h and then concentrated under reduced pressure. The residue was purified by prep-HPLC (Instrument: Biotage Isolera Prime; Column: Phenomenex Luna C 18, 150 × 25 mm, 10 pm; Mobile phase: A = water (0.1% formic acid), B = acetonitrile; Gradient: 5-40% B over 10 min; Flow rate: 60 mL / min) to afford the title compound. LC-MS (ESI+): m / z = 295.0 [M+H]+.

[0359] Synthesis of methyl 3-(7-ethynyl-l-oxoisoindolin-2-yl)benzoate (Intermediate 1.25)

[0360] Step 1: Synthesis of methyl 3-(7-ethynyl-l-oxoisoindolin-2-yl)benzoate

[0361] To a solution of methyl 3-(l-oxo-7-((trimethylsilyl)ethynyl)isoindolin-2-yl)benzoate (1.40 g, 3.85 mmol, from Intermediate 1.22) in MeOH (14 mL) was added K2CO3 (1.06 g, 7.70 mmol). The mixture was stirred at room temperature (20 °C) for 1 hour. Upon completion, the mixture was filtered, and the filtrate was concentrated under reduced pressure to afford the title compound. LC-MS (ESI+): m / z = 292.1 [M+H] ‘HNMR (400 MHz, DMSO-de): 8 = 8.66-8.56 (m, 1H), 8.15-8.01 (m, 1H), 7.80-7.73 (m, 1H), 7.71-7.53 (m, 5H), 5.08-5.00 (m, 2H), 3.89 (s, 3H).

[0362] Synthesis of 7-bromo-2-(3-(4-methyl-177-l,2,3-triazol-l-yl)phenyl)isoindolin-l-one (Intermediate 1.26)DB1 / 166057797.1Docket No. 133447-5010-WO

[0363] Step 1: Synthesis of 1 -(3 -brom ophenyl)-4-m ethyl- 177-1, 2, 3-triazole

[0364] To a solution of l,l-dimethoxy-2-propanone (2.10 g, 17.8 mmol) in DMSO (30 mL) was added -toluenesulfonyl hydrazide (3.31 g, 17.8 mmol). The mixture was stirred at room temperature (20 °C) for 1 hour. 3 -Bromoaniline (3.06 g, 17.8 mmol) was then added, and the reaction mixture was stirred at 80 °C for 2 hours. Upon completion, the mixture was diluted with H2O (80 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (Instrument: Biotage Isolera Prime; Column: 40 g SepaFlash® Silica Flash Column; Mobile phase: A = hexane, B = EtOAc; Gradient: 10-25% B over 10 min; Flow rate: 80 mL / min) to afford the title compound. LC-MS (ESI+): m / z = 240.0 [M+H]+.1H NMR (400 MHz, CDCh): 5 = 7.92 (s, 1H), 7.73 (s, 1H), 7.68 (dd, J = 1.2, 8.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.42-7.36 (m, 1H), 2.45 (s, 3H).

[0365] Step 2: Synthesis of 3-(4-methyl-177-l,2,3-triazol-l-yl)phenyl Zc / v-butylcarbamate

[0366] A mixture of 1 -(3 -bromophenyl)-4-m ethyl- 117-1, 2, 3-triazole (2.70 g, 11.3 mmol), / c / V-butyl carbamate (1.99 g, 17.0 mmol), XPhos Pd G3 (961 mg, 1.13 mmol), XPhos (1.08 g, 2.27 mmol), and CS2CO3 (11.1 g, 34.0 mmol) in 1,4-dioxane (27 mL) was degassed and purged with N2 three times. The mixture was stirred at 85 ...

Claims

Docket No. 133447-5010-WOCLAIMS1. A compound of formula (IA), or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof:Ai is CR1or N;A2 is CR2or N;A3 is CR3or N;R1, R2, and R3are each independently selected from H, deuterium, halide, -CN, -ORa, -N(Ra)2, -NO2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 6-membered heterocycloalkyl;ring A is aryl or heteroaryl;ring B is selected from aryl, cycloalkyl, heteroaryl, and heterocycloalkyl;R4and R5are independently at each occurrence selected from optionally substituted 5- to 12-membered heteroaryl, deuterium, halide, -CN, trimethylsilanyl, oxo, -ORa, -SRa, - S(O)tRa, -OC(O)Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -NO2, -OC(O)N(Ra)2, - N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, - C(O)N(Ra)S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, -S(O)tN(Ra)C(O)Ra, -P(O)(ORa)2, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-Ce alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heteroalkyl, and optionally substituted 3- to 12-membered heterocycloalkyl;m and n are each independently selected from 1, 0, 2, 3, and 4;DB1 / 166057797.1Docket No. 133447-5010-WOt is 1 or 2;R6and R6'are each independently selected from optionally substituted C1-C6alkyl, H, deuterium, halide, -CN, -ORa, -N(Ra)2, optionally substituted Ci-Ce haloalkyl, optionally substituted C6-C12 aryl, optionally substituted C3-C8cycloalkyl, optionally substituted3- to 8-membered heteroalkyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocycloalkyl; or R6and R6'are taken together to form =C(Rb)2;Rais independently at each occurrence selected from H, deuterium, -OH, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-Ce haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl; or two Ragroups are taken together with the atom to which they are attached to form optionally substituted 5- to 6-membered heteroaryl or optionally substituted3- to 6-membered heterocycloalkyl; andRbis independently at each occurrence selected from H, deuterium, halide, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C8cycloalkyl, optionally substituted 3- to 8-membered heteroalkyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted3- to 12-membered heterocycloalkyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein R1, R2, and R3are each independently selected from H, halide, -CN, -ORa, -N(Ra)2, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 haloalkyl, optionally substituted phenyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted5- to 6-membered heteroaryl, and optionally substituted 3- to 6-membered heterocycloalkyl.

3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein R1, R2, and R3are eachDB1 / 166057797.1Docket No. 133447-5010-WOindependently selected from H, halide, -ORa, -N(Ra)2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 haloalkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 5-membered heterocycloalkyl.

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein ring A is phenyl or5- to 6-membered heteroaryl.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein ring B is selected from aryl, heteroaryl, and heterocycloalkyl.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein R4is independently at each occurrence selected from halide, -CN, oxo, -ORa, -SRa, -S(O)tRa, -OC(O)Ra, -N(Ra)2, -C(O)Ra, - C(O)ORa, -C(O)N(Ra)2, -NO2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa, -C(O)N(Ra)S(O)tRa, -S(O)tORa, - S(O)tN(Ra)2, -S(O)tN(Ra)C(O)Ra, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocycloalkyl.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein R5is independently at each occurrence selected from halide, -CN, trimethylsilanyl, oxo, -ORa, -SRa, -S(O)tRa, -OC(O)Ra, - N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -NO2, -OC(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -C(O)N(Ra)S(O)tRa, -S(O)tORa, - S(O)tN(Ra)2, -S(O)tN(Ra)C(O)Ra, -P(O)(ORa)2, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C8 DB1 / 166057797.1Docket No. 133447-5010-WOcycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted5- to 12-membered heteroaryl, and optionally substituted 3- to 12-membered heterocycloalkyl.

8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein m is 1, 2, 3, or 4.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein n is 1, 2, 3, or 4.

10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein R6and R6are each independently selected from H, deuterium, halide, -CN, -ORa, -N(Ra)2, optionally substituted Ci- C4 alkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl; or R6and R6' are taken together to form =C(Rb)2.

11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein R6and R6'are each independently selected from H, deuterium, halide, -CN, -ORa, -N(Ra)2, optionally substituted C1-C3alkyl, optionally substituted C1-C3haloalkyl, optionally substituted phenyl, optionally substituted C3-C6cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 8-membered heterocycloalkyl; or R6and R6'are taken together to form =C(Rb)2.

12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein Rais independently at each occurrence selected from H, -OH, optionally substituted C1-C4 alkyl, optionally substitutedDB1 / 166057797.1Docket No. 133447-5010-WOC1-C4 haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl; or two Ragroups are taken together with the atom to which they are attached to form optionally substituted5- to 6-membered heteroaryl or optionally substituted 3- to 6-membered heterocycloalkyl.

13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein the compound has a structure according to formula (IIA):wherein in formula (IIA):Ai is N or CR1;A2 is N or CR2;A3is N or CR3;R1, R2, and R3are each independently selected from H, halide, -ORa, -N(Ra)2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 haloalkyl, optionally substituted C3-C5 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted5- to 6-membered heteroaryl, and optionally substituted 3- to 5-membered heterocycloalkyl;A4 is N or CR41;As is N or CR51;Yi and Y2 are each independently selected from N and CRY; or Yi is absent, and Y2 is selected from NRb, O, and S;R41, R51, and RYare each independently selected from H, halide, -CN, -ORa, -S(O)tRb, - OC(O)Rb, -N(Rb)2, -C(O)Rb, -C(O)N(Rb)2, -N(Ra)C(O)Rb, -S(O)tN(Rb)2, optionally substitutedDB1 / 166057797.1Docket No. 133447-5010-WOC1-C3 alkyl, optionally substituted C1-C3 haloalkyl, optionally substituted C3-C4 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, and optionally substituted3- to 4-membered heterocycloalkyl;ring B is selected from phenyl, 5- to 6-membered heteroaryl, and 3- to 10-membered heterocycloalkyl;R4is selected from -S(O)tRa, -OC(O)Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)Ra, -N(Ra)S(O)tRa, -C(O)N(Ra)S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, -S(O)tN(Ra)C(O)Ra, substituted C1-C4 alkyl, substituted C6-C10aryl, substituted C3-C8 cycloalkyl, substituted 5- to 10-membered heteroaryl, and substituted 3- to 10-membered heterocycloalkyl;R5is independently at each occurrence selected from halide, -CN, oxo, -ORa, -SRa, - S(O)tRa, -OC(O)Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -NO2, -OC(O)N(Ra)2, - N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, - C(O)N(Ra)S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, -S(O)tN(Ra)C(O)Ra, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl;n is 1, 2, or 3;t is 1 or 2;R6and R6are each independently selected from H, deuterium, halide, -CN, -ORa, - N(Ra)2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 haloalkyl, optionally substituted phenyl, optionally substituted C3-C6 cycloalkyl, optionally substituted3- to 6-membered heteroalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 8-membered heterocycloalkyl; or R6and R6'are taken together to form =C(Rb)2;Rais independently at each occurrence selected from H, -OH, optionally substituted Ci- C4 alkyl, optionally substituted C1-C4 haloalkyl, optionally substituted phenyl, optionally substituted C3-C4, cycloalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 6-membered heterocycloalkyl; or two Ragroups are taken together with the atom to which they are attached to form optionally substituted 5- to 6-membered heteroaryl or optionally substituted 3- to 6-membered heterocycloalkyl; andDB1 / 166057797.1Docket No. 133447-5010-WORbis independently at each occurrence selected from H, deuterium, halide, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 haloalkyl, optionally substituted phenyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 6-membered heterocycloalkyl.

14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein R4is selected from - S(O)tRa, -N(Ra)2, -C(O)Ra, -C(O)N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa, -S(O)tN(Ra)2, - S(O)tN(Ra)C(O)Ra, substituted phenyl, substituted C4-C8 cycloalkyl, substituted5- to 6-membered heteroaryl, and substituted 4- to 8-membered heterocycloalkyl.

15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein R4is selected from - C(O)Ra, -C(O)N(Ra)2, -N(Ra)C(O)Ra, -S(O)tN(Ra)2, C4-C8cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 8-membered heterocycloalkyl;wherein at least one ring atom of cycloalkyl, heteroaryl, and heterocycloalkyl is substituted with an oxo group, and the cycloalkyl, heteroaryl, and heterocycloalkyl are optionally further substituted with one, two, or three Rcgroups; andRcis independently at each occurrence selected from halide, -CN, -ORa, -N(Ra)2, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl.DB1 / 166057797.1Docket No. 133447-5010-WO16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein R4is a moiety of formula (IIIA):(IIIA),wherein in formula (IIIA):- is a single bond or a double bond;Ae is selected from N, C, and CH;X is selected from NRdor N; C(Rd)2 or CRd; O; and S;Zi, Z2, and Z3 are each independently selected from NRd, N, C(Rd)2, CRd, C(O), O, and S; p and q are each independently selected from 0 and 1; andRdis independently at each occurrence selected from H, halide, -CN, -ORa, -N(Ra)2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 haloalkyl, optionally substituted phenyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 6-membered heterocycloalkyl.

17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein the compound has a structure according to formula (IVA):(IVA),DB1 / 166057797.1Docket No. 133447-5010-WOwherein in formula (IVA):ring B is selected from phenyl, pyridine, pyrazine, pyrimidine, pyridazine, triazine, tetrazine.

18. The compound of any one of claims 13 to 17, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein A4 is CR41; A5 is CR51; Yi is CRY; and Y2 is CRY.

19. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein R4is a moiety of formula (VA):ORx JNHN^ / *Rd(VA),wherein in formula (VA):Rdis independently at each occurrence selected from H, halide, -ORd', optionally substituted C1-C3alkyl, -CD3, C1-C2haloalkyl, optionally substituted C3-C5cycloalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 5-membered heterocycloalkyl; and Rd'is independently at each occurrence selected from H, optionally substituted C1-C3alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl.

20. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein the compound has a structure according to formula (VIA):DB1 / 166057797.1Docket No. 133447-5010-WOO R51R41R3R2wherein in formula (VIA):R1is selected from H, halide, and optionally substituted C1-C3 alkyl;R2is selected from H, halide, -CN, -OH, -OCH3, -NH2, -N(CHs)2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 haloalkyl, optionally substituted C3-C4 cycloalkyl, and optionally substituted 3- to 4-membered heterocycloalkyl;R3is selected from H, halide, and optionally substituted C1-C3 alkyl;R41is selected from H, F, Cl, Br, -CN, -OCH3, -S(O)2CH3, -C(O)CH3, -CH3, -CH2CH3, - CH2CH2CH3, -CH2CH(CH3)2, and -CH2N(CH3)2;R51is selected from H, F, Cl, Br, -CN, -OCH3, -S(O)2CH3, -C(O)CH3, -CH3, -CH2CH3, - CH2CH2CH3, -CH2CH(CH3)2, and -CH2N(CH3)2;R' are each independently selected from H, F, Cl, Br, -CN, -OCH3, -S(O)2CH3, - C(O)CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH(CH3)2, and -CH2N(CH3)2;Rdis independently at each occurrence selected from H, halide, -ORd', optionally substituted C1-C3alkyl, -CD3, C1-C2haloalkyl, optionally substituted C3-C5cycloalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 5-membered heterocycloalkyl; Rd'is independently at each occurrence selected from H, optionally substituted C1-C3alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl;R5is independently at each occurrence selected from halide, -CN, oxo, -ORa, -SRa, - S(O)tRa, -OC(O)Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -NO2, -OC(O)N(Ra)2, - N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, -N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa, -DB1 / 166057797.1Docket No. 133447-5010-WOC(O)N(Ra)S(O)tRa, -S(O)tORa, -S(O)tN(Ra)2, -S(O)tN(Ra)C(O)Ra, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 3- to 10-membered heterocycloalkyl;n is 1, 2, or 3;t is 1 or 2;R6and R6are each independently selected from H, deuterium, halide, -CN, -ORa, -N(Ra)2, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 haloalkyl, optionally substituted phenyl, optionally substituted C3-C6 cycloalkyl, optionally substituted3- to 6-membered heteroalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 8-membered heterocycloalkyl; or R6and R6'are taken together to form =C(Rb)2; andRais independently at each occurrence selected from H, -OH, optionally substituted Ci- C4 alkyl, optionally substituted C1-C4 haloalkyl, optionally substituted phenyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 6-membered heterocycloalkyl; or two Ragroups are taken together with the atom to which they are attached to form optionally substituted 5- to 6-membered heteroaryl or optionally substituted 3- to 6-membered heterocycloalkyl.

21. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein R4is a moiety of (VIIA):°^Rd’ (VIIA),wherein in formula (VIIA):Rdis selected from H, optionally substituted C1-C3 alkyl, -CD3, optionally substituted C3- C4 cycloalkyl, and optionally substituted 3- to 4-membered heterocycloalkyl; andDB1 / 166057797.1Docket No. 133447-5010-WORd'is selected from H, optionally substituted C1-C3 alkyl, optionally substituted C3-C8 cycloalkyl, and optionally substituted 3- to 10-membered heterocycloalkyl.

22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein the compound has a structure according to formula (VIIIA):wherein in formula (VIIIA):R2is selected from H, Cl, Br, F, -CN, -OCH3, -N(CH3)2, -CH3, -CF3, cyclopropyl, and oxetanyl;Rdis selected from H, optionally substituted C1-C3 alkyl, -CD3, optionally substituted C3- C4 cycloalkyl, and optionally substituted 3- to 4-membered heterocycloalkyl;Rd’ is selected from H, optionally substituted C1-C3 alkyl, optionally substituted C3-C8 cycloalkyl, and optionally substituted 3- to 10-membered heterocycloalkyl;R5is independently at each occurrence selected from F, -CN, -CH3, -C(O)N(R5a)2, optionally substituted C3-C8 cycloalkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted 3- to 8-membered heterocycloalkyl;R5ais independently at each occurrence selected from H, optionally substituted C1-C3 alkyl, optionally substituted 5- to 6-membered heteroaryl, and optionally substituted3- to 6-membered heterocycloalkyl;n is 1, 2, or 3;R6and R6are each independently selected from H, deuterium, halide, -CN, -OR6a, - NHR6a, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 haloalkyl, optionallyDB1 / 166057797.1Docket No. 133447-5010-WOsubstituted phenyl, optionally substituted C3-C6 cycloalkyl, optionally substituted5- to 6-membered heteroaryl, and optionally substituted 3- to 8-membered heterocycloalkyl; or R6and R6’ are taken together to form =C(R6b)2;R6ais independently at each occurrence selected from H, optionally substituted C1-C3 alkyl, optionally substituted C1-C4 haloalkyl, C3-C6 cycloalkyl, and 3- to 6-membered heterocycloalkyl; andR6bis independently at each occurrence selected from H, deuterium, halide, C1-C3 alkyl, and C1-C3 haloalkyl.

23. A pharmaceutical composition comprising a compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, and a physiologically compatible carrier medium.

24. A method of treating a disease or disorder in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-22, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.

25. A method of treating a disease or disorder in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of claim 23.

26. The method of claim 24 or claim 25, wherein the disease or disorder is selected from an allergic disease, an inflammatory disease, and an autoimmune disease.

27. The method of any one of claims 24 to 26, wherein the disease or disorder is alleviated by inhibiting signal transducer and activator of transcription (STAT) protein activity in the patient.DB1 / 166057797.1Docket No. 133447-5010-WO28. The method of any one of claims 24 to 27, wherein the disease or disorder is alleviated by inhibiting STAT6 protein activity in the patient.

29. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein the compound has a cellular activity of at least about 10 μM as measured by an in vitro cellular assay.

30. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt, solvate, tautomer, isomer, hydrate, cocrystal, or prodrug thereof, wherein the compound has a Kd of about 1 pM or less.DB1 / 166057797.1

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